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Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma
Abstract
The young age of neuroblastoma patients makes them especially prone to the ototoxic effects of widely used treatments that feature aggressive use of platinum compounds. We present data defining the extent of the problem in a large series of neuroblastoma patients whose induction included high-dose cisplatin/etoposide (HD-P/E) as used in both the Memorial Sloan-Kettering Cancer Center N7 regimen and the Children's Oncology Group A3973 study.
N7/A3973 patients were divided into 3 groups: Group 1 had hearing tested after induction, that included 2 cycles of HD-P/E (cumulative cisplatin = 400 mg/m(2)); Group 2 had hearing tested after induction, that included 3 cycles of HD-P/E (cumulative cisplatin = 600 mg/m(2)); and Group 3 had hearing tested following carboplatin-containing myeloablative therapy administered after induction, that included 2 cycles of HD-P/E. Ototoxicity was scored by the Brock method.
All 3 groups had similar clinical characteristics, including median age at diagnosis of about 3 years. Little or no hearing loss in the speech range (Grade 0/1) was documented in 21 (32%) of the 65 Group 1 patients, 5 (10%) of the 50 Group 2 patients, and 9 (15.5%) of the 58 Group 3 patients. Severe (Grade 3/4) deficits affected 25% of Group 1, 54% of Group 2, and 50% of Group 3 patients. Patients < 5 years at diagnosis had greater ototoxicity than older patients had, with adolescents/adults being the least affected. Findings were stable in repeated assessments over 2 or more years.
Ototoxicity is a serious and pervasive problem in this patient population. Strategies to ameliorate ototoxicity without compromising on antitumor activity of treatments are urgently needed.
... In contrast, our study revealed that over half of the children treated for HB suffered from impaired hearing (Boston score > 1) and one third from severe hearing loss (Boston score 3 + 4). The is in line with previous studies, and the dosage of cisplatin has been an important focus in recent trial designs [19,20,22,27,28]. Studies have shown that cisplatin-induced hearing loss in paediatric patients usually occurs following cumulative doses exceeding 400 mg/m 2 [27,[29][30][31]. ...
... The is in line with previous studies, and the dosage of cisplatin has been an important focus in recent trial designs [19,20,22,27,28]. Studies have shown that cisplatin-induced hearing loss in paediatric patients usually occurs following cumulative doses exceeding 400 mg/m 2 [27,[29][30][31]. This is also seen among other paediatric tumours, e.g., neuroblastomas and brain tumours [27]. ...
... Studies have shown that cisplatin-induced hearing loss in paediatric patients usually occurs following cumulative doses exceeding 400 mg/m 2 [27,[29][30][31]. This is also seen among other paediatric tumours, e.g., neuroblastomas and brain tumours [27]. In contrast, our study indicated that the children with impaired hearing function received comparable cumulative doses of cisplatin to children with normal hearing function, but our sample size was small. ...
Background:
Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events.
Methods:
We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome.
Results:
We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children.
Conclusions:
In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients.
... Cranial irradiation (base of skull) can worsen this irreversible hearing loss [29]. However, most clinical protocols contain a combination of cisplatin and at least one more cytotoxic drug [28,[40][41][42], a combination with other neurotoxic agents [14,40,42,43], and/or a radiation treatment to the head and neck region or base of skull [44]. For patients undergoing chemoradiation for head and neck malignancies, multivariate analysis indicated that cumulative cisplatin dose, radiation-induced secretory otitis media, and the dose to 0.1 cc (D0.1cc) to the cochlea are factors predicting sensorineural hearing loss [45]. ...
... Cranial irradiation (base of skull) can worsen this irreversible hearing loss [29]. However, most clinical protocols contain a combination of cisplatin and at least one more cytotoxic drug [28,[40][41][42], a combination with other neurotoxic agents [14,40,42,43], and/or a radiation treatment to the head and neck region or base of skull [44]. For patients undergoing chemoradiation for head and neck malignancies, multivariate analysis indicated that cumulative cisplatin dose, radiation-induced secretory otitis media, and the dose to 0.1 cc (D0.1cc) to the cochlea are factors predicting sensorineural hearing loss [45]. ...
... With increasing cumulative doses from 400 to 600 mg, there is a doubled risk for grade 3 and 4 ototoxicity [51]. The reported cumulative doses of cisplatin differ considerably, between 200-800 mg/m 2 [22,40]. With a mean dose of 336 mg cisplatin, the dose was below the level of 400 mg. ...
Objective
This study aimed to evaluate subjective and objective hearing loss in cervical cancer patients after chemoradiation with cisplatin (mono).
Patients and methods
A total of 51 cervical cancer patients with indication for chemoradiation were included. Pure tone and impedance audiometry were performed before and after chemoradiation. Hearing loss was scaled according to ASHA criteria. Subjective hearing was assessed with the Oldenburger Sentence Test. To consider age-dependent changes, hearing loss was corrected for age and the time interval between measurements.
Results
Median age at diagnosis was 46 years, 46% were active/former smokers (n = 24), 28 (54%) patients were never-smokers. Median total weekly cisplatin dose was 70 ± 14.2 mg. Cumulative doses of cisplatin during chemoradiation ranged between 115.2 and 400 mg cisplatin (mean 336.1 mg, median 342 ± 52.7 mg). The median interval between last chemotherapy and second audiometry was 320 ± 538 days (35–2262 days). Changes in hearing threshold ≥20 dB were experienced by 32/52 patients (62%) following chemoradiation, 55% of them for frequencies ≥6000 Hz. No statistically significant hearing loss remained after chemoradiation upon correction for age and time interval. Patients >40 years had a higher risk of hearing loss than younger patients. Objective data on hearing function did not correlate with subjective hearing loss and did not impair daily activity in any patient.
Conclusion
Chemoradiation with cumulative cisplatin doses up to 400 mg did not lead to significant impairment of objective or subjective hearing. For cervical cancer patients undergoing chemoradiation, standard audiometry is not indicated.
... This result confirms the dose-dependent effect of cisplatin in inducing ototoxicity that has been reported by others. 7,17 The progression of hearing impairment in our study occurred as early as 3 months after the first dose of cisplatin and 43.9% of patients progressed ≥2 grades of CTCAE v.5, which was associated with them having received a higher cisplatin dose. However, the progression of significant hearing impairment in our study occurred as late as 37 months. ...
... Another significant risk factor in our study was a young age of ≤5 years old, which correlated with previous literature. 6,7,17 However, the multivariable analysis in our study did not show the younger age as significant. This could be due to the small number of this population (31.9%). ...
Background:
Hearing is essential in child development. Cisplatin which is a common chemotherapy used in many pediatric solid-tumor protocols cause various degrees of ototoxicity. Several risk factors for cisplatininduced ototoxicity have been reported, including race and age. This study aimed to evaluate the incidence of ototoxicity and its long-term outcome in Thai pediatric solid-tumor patients receiving cisplatin and to determine the risk factors associated with hearing impairment.
Methods:
A retrospective study was conducted in solid-tumor patients < 15 years old from 2007 to 2019 at Siriraj Hospital, Bangkok, Thailand. Hearing was evaluated by an audiogram and/or auditory steady-state response and the impairment was graded according to the Common Terminology Criteria for Adverse Events version 5. Grade 2 and above was considered significant hearing loss.
Results:
In total, the hearing of 47 patients was evaluated. At the end of treatment, hearing impairment and significant hearing loss were found in 66% and 48.9% of patients, respectively. A high median cumulative cisplatin dose was significantly associated with worse hearing impairment (p = 0.039) and a more progressive grading of ototoxicity (p = 0.005). A risk factor for significant hearing loss was a cumulative dose ≥400 mg/m2 (p = 0.014). All 9 patients who received a cumulative dose > 600 mg/m2 and 5 patients who received aminoglycoside developed significant hearing loss. One patient had progressive hearing impairment at 8 months after the end of treatment and 1 patient developed grade 3 ototoxicity which required a hearing aid after bone marrow transplantation. The latter patient received a total cisplatin dose of 708.2 mg/m < sup > 2 < /sup > and carboplatin 1400 mg/m < sup > 2 < /sup > .
Conclusions:
The incidence of hearing impairment in pediatric patients receiving cisplatin is high. Regular hearing evaluation is essential for the early detection of ototoxicity. Long-term follow-up is recommended, especially in patients who have a combination of other risk factors for hearing loss.
... However, patients treated with cisplatin frequently suffer from nausea, vomiting, fatigue, serious kidney problems, tinnitus and hearing loss. The strong ototoxicity of cisplatin, which leads to the permanent hair cell death and irreversible hearing loss in 22-77% of patients, significantly limits its usage in clinics (Knight et al., 2005;Kushner et al., 2006;Coradini et al., 2007;Sheth et al., 2017;Kros and Steyger, 2019;Meijer et al., 2021). ...
... Sensorineural hearing loss occurs in 22-77% of patients treated with cisplatin (Knight et al., 2005;Kushner et al., 2006;Coradini et al., 2007;Sheth et al., 2017;Kros and Steyger, 2019). Patients suffering hearing loss nowadays benefit from FIGURE 1 | Cisplatin dose-dependently kills wild-type murine hair cells. ...
Cisplatin is one of the most widely used chemotherapeutic drugs across the world. However, the serious ototoxic effects, leading to permanent hair cell death and hearing loss, significantly limit the utility of cisplatin. In zebrafish, the functional mechanotransduction channel is required for cisplatin ototoxicity. However, it is still unclear the extent to which the mechanotransduction channel is involved in cisplatin uptake and ototoxicity in mammalian hair cells. Herein, we show that genetically disrupting mechanotransduction in mouse partially protects hair cells from cisplatin-induced hair cell death. Using a fluorescent-dye conjugated cisplatin, we monitored cisplatin uptake in cochlear explants and found that functional mechanotransduction is required for the uptake of cisplatin in murine hair cells. In addition, cimetidine, an inhibitor of the organic cation transporter, also partially protects hair cells from cisplatin ototoxicity. Notably, the otoprotective effects of cimetidine do not require mechanotransduction. These findings suggest that both the mechanotransduction channel and the organic cation transporter are critical for cisplatin ototoxicity in murine hair cells.
... 9 Risk factors for developing CIHL are not well-characterized; apart from cumulative cisplatin dose, very few risk factors for CIHL have been consistently identified across case series. 3,[9][10][11][12][13][14] Identification of populations and risk factors for CIHL from past reports is complicated by studies with relatively small numbers of cisplatin-treated patients, single-institution cohorts, and variability among studies in timing of audiology assessments, methods of audiologic evaluation, and even the definition of hearing loss. [9][10][11][12]14 Similarly, genomic studies of pediatric CIHL have used relatively small and varied cohorts, regimens, and hearing endpoints. ...
... 3,[9][10][11][12][13][14] Identification of populations and risk factors for CIHL from past reports is complicated by studies with relatively small numbers of cisplatin-treated patients, single-institution cohorts, and variability among studies in timing of audiology assessments, methods of audiologic evaluation, and even the definition of hearing loss. [9][10][11][12]14 Similarly, genomic studies of pediatric CIHL have used relatively small and varied cohorts, regimens, and hearing endpoints. The resultant inconsistent phenotyping has resulted in few genes implicated in CIHL being replicated among studies. ...
Background
Cisplatin is used to treat a wide range of childhood cancers and cisplatin-induced hearing loss (CIHL) is a common and debilitating toxicity. We aimed to address persistent knowledge gaps in CIHL by establishing benchmarks for the prevalence of and risk factors for CIHL.
Methods
In this multi-institutional cohort study, children (age 0–14 years), adolescents, and young adults (age 15–39 years) diagnosed with a cisplatin-treated tumour from paediatric cancer centres, who had available cisplatin dosing information, and primary audiology data for central review from consortia located in Canada and the USA were eligible for inclusion. Audiology was centrally reviewed and CIHL graded using the consensus International Society of Pediatric Oncology (SIOP) Boston Ototoxicity Scale. We assessed the prevalence of moderate or severe CIHL (SIOP grade ≥2) at latest follow-up and end of therapy, in each demographic, diagnosis, and treatment group and their relative contributions to risk for CIHL. Secondary endpoints explored associations of cisplatin dose reductions and CIHL with survival. We also examined whether cisplatin dose reductions and CIHL were associated with survival outcomes.
Findings
We included 1481 patients who received cisplatin. Of the 1414 (95·5%) participants who had audiometry at latest follow-up (mean 3·9 years [SD 4·2] since diagnosis), 620 (43·8%) patients developed moderate or severe CIHL. The highest prevalence of CIHL was seen in the youngest patients (aged <5 years; 360 [59·4%] of 606 patients) and those with a CNS tumour (221 [50·9%] of 434 patients), hepatoblastoma (110 [65·9%] of 167 patients), or neuroblastoma (154 [62·1%] of 248 patients). After accounting for cumulative cisplatin dose, higher fractionated doses were associated with risk for CIHL (for each 10mg/m² increase per day, adjusted odds ratio [aOR] 1·15 [95% CI 1·07–1·25]; for each 50 mg/m² increase per cycle aOR 2·16 [1·37–3·51]). Vincristine exposure was newly identified as a risk factor for CIHL (aOR 3·55 [2·19–5·84]). Dose reductions and moderate or severe CIHL were not significantly associated with survival differences.
Interpretation
Using this large, multicentre cohort, benchmarks were established for the prevalence of CIHL in patients treated with cisplatin. Variations in cisplatin dosing confer additive risk for developing CIHL and warrant investigation as a potential approach to decrease the burden of therapy.
Funding
US National Institutes of Health and National Institute on Deafness and Other Communication Disorders, US National Institutes of Health and National Cancer institute, St Baldrick's Foundation, Genome Canada, Genome British Columbia, Canadian Institutes of Health Research, the Canada Foundation for Innovation, University of British Columbia, British Columbia Children's Hospital Research Institute, British Columbia Provincial Health Services Authority, Health Canada, and C17 Research Network.
... Hearing toxicity related with cisplatin is usually bilateral, irreversible and sensorineural in type in high frequencies [2][3][4]. The factors those affect ototoxicity are cumulative and repeating cisplatin doses, age less than 5 years, co-existence of renal disease, cranial irradiation and other autotoxic drugs such as aminoglycoside and furocemid [5][6][7][8]. Some adult and pediatric studies demonstrated that cisplatin ototoxicity might be related with DDIT4, NEK2, MYC genes, megalin, glutation S-transpherase, TPMT (Tiopurin-S-Metiltranspherase), COMT (Catechol-O-methyltransferase), ACYP2, GJB2, and SLC26A4 gene polymorphisms [9][10][11][12][13][14]. ...
... Cisplatin-induced ototoxicity is frequently bilateral, irreversible, and sensorineural in high frequencies. Speech and language development may be impaired as a result of hearing loss, and this may [3,5,6]. Cumulative cisplatin doses were similar in the patient group with or without hearing loss (p = 0.67 and p = 0.59, respectively). ...
Purpose
We aimed to investigate the cisplatin-related hearing toxicity and its possible relationship with polymorphic variants in DNA repair genes, ERCC1, ERCC2, and XRCC1.
Methods
Fifty patients treated with cisplatin in the past were included in the study. There were 29 females and 21 males; mean age 13.4 ± 6.0 years). The polymorphism in DNA repair genes was studied using primer and probes in Light Cycler device after DNA isolation was carried out with PCR technique. The polymorphisms and clinical risk factors were evaluated using Chi square test and logistic regression modelling.
Results
The patients had hearing loss in 44%. For ERCC1 gene, the patients with hearing loss had 50% of GG (wild type), 40.9% of AG and 9.1% of AA genotypes, while the patients without hearing loss had 28.6% of GG, 53.5% of AG, and 17.9% of AA genotypes. For ERCC2 gene, the patients with hearing loss had 18.2% of GG (wild type), 40.9% of TG, and 40.9% of TT genotypes, while the patients without hearing loss had 10.7% of GG 39.3% of TG, and 50% of TT genotypes. For XRCC1 gene, the patients with hearing loss had 18.2% of CC (wild type), 59.1% of CT, and 22.7% of TT genotypes, while the patients without hearing loss had 35.7% of CC, 50% of CT, and 14.3% of TT genotypes. There was no statistically significant association among the groups (p = 0.24).
Conclusion
We did not find a relationship between DNA repair gene polymorphisms and hearing toxicity of cisplatin.
... However, with regard to cumulative cisplatin dose, the present study found a relatively lower cumulative cisplatin dose (200 mg/m 2 ) to be associated with hearing loss, when compared to 400 mg/m 2 , which is reported by other scholars in the field. 13,22,23 Patient factors such as age and sex have also been identified as risk factors for developing hearing loss. 12 Association between younger age and a higher likelihood of developing hearing loss was reported in previous studies. ...
... 12 Association between younger age and a higher likelihood of developing hearing loss was reported in previous studies. 15,23 In the present study, children below the age of 10 years were more likely to develop hearing loss when compared to those above 10 years. However, this was not found to be statistically significant, possibly because of the small sample size of the current study. ...
This paper reports on the risk factors for developing ototoxic hearing loss in South African paediatric oncology patients undergoing cisplatin-based chemotherapy.
... Estimates suggest that some degree of cisplatin-induced hearing loss (CIHL) develops in 50%-70% of treated children. [1][2][3][4][5][6] The main mechanism whereby cisplatin damages the inner ear is the formation of high levels of reactive oxygen species (ROS), eventually resulting in cochlear hair cell apoptosis. 7,8 Hearing loss related to carboplatin treatment is also observed, but the overall prevalence is lower (0%-25%). ...
PURPOSE
Hearing loss occurs in 50%-70% of children treated with cisplatin. Scientific efforts have led to the recent approval of a pediatric formula of intravenous sodium thiosulfate (STS) for otoprotection by the US Food and Drug Administration, the European Medicines Agency, and the Medicines and Health Regulatory Authority in the United Kingdom. To inform stakeholders regarding the clinical utility of STS, the current review summarizes available literature on the efficacy, pharmacokinetics (PK), and safety of systemic STS to minimize cisplatin-induced hearing loss (CIHL).
DESIGN
A comprehensive narrative review is presented.
RESULTS
Thirty-one articles were summarized. Overall, systemic STS effectively reduces CIHL in the preclinical and controlled clinical study settings, in both adults and children with cancer. The extent of CIHL reduction depends on the timing and dosing of STS in relation to cisplatin. Both preclinical and clinical data suggest that systemic STS may affect plasma platinum levels, but studies are inconclusive. Delayed systemic administration of STS, at 6 hours after the cisplatin infusion, does not affect cisplatin-induced inhibition of tumor growth or cellular cytotoxicity in the preclinical setting, nor affect cisplatin efficacy and survival in children with localized disease in the clinical setting.
CONCLUSION
Systemic administration of STS effectively reduces the development and degree of CIHL in both the preclinical and clinical settings. More studies are needed on the PK of STS and cisplatin drug combinations, the efficacy and safety of STS in patients with disseminated disease, and the ability of STS to prevent further deterioration of pre-established hearing loss.
... Следует отметить, что результаты многих исследований демонстрируют различные данные о частоте встречаемости ОПЭ у пациентов с НБ [7][8][9][10][11]. Однако наиболее частыми патологиями у данной группы больных являются снижение слуха, эндокринные осложнения и ортопедические нарушения [9,[12][13][14]. ...
Neuroblastoma (NB) is the most common extracranial solid tumor in children. The stratification of patients into risk groups has
led to the development of therapeutic protocols with intensification of therapy in high-risk patients and minimal treatment, up to the complete abandonment of chemotherapy in patients with a potentially favorable long-term prognosis. The implementation of multimodal therapy in the intermediate/high-risk group patients significantly improved long-term survival rates. However, anticancer treatment inevitably leads to a wide range of undesirable effects and long-term consequences, including negative effects on the musculoskeletal tissue and teeth. The main factors leading to the pathology of the musculoskeletal system include chemotherapy, including high-dose chemotherapy with autologous hematopoietic stem cell transplantation, radiation
therapy and other methods of treatment. In addition, the localization of a primary tumor and metastases creates a potential
threat of the development of undesirable effects on the musculoskeletal system, including for patients from the observation group. The article presents a description of clinical cases of musculoskeletal toxicity in patients with NB who completed specific treatment with a literature review on this topic. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.
... Anywhere from 20% to 70% of patients experience CDDP-related ototoxicity, with this effect being more prominent in children [168,169]. CDDP induces ototoxicity through induction of ROS and apoptotic cell death within the hair cells of the ear [170,171]. As a result, 40-80% of patients develop permanent hearing loss [172]. ...
Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.
... Cumulative dose of cisplatin (mg) X 2 P value <400 >400 of developing moderate to severe HL from cisplatin than their adult counterparts. [23,24] Although the ototoxicity experienced by older patients is often reported as less severe in terms of grading scales, HL may progress in all patients over time independently of or synergistically with exposure to other hearing insults. [17] Bertolini et al [1] reported a HL of Grade ≥ 2 in 11% of patients within 2 years of the end of therapy. ...
Hearing damage is one of the main toxic effects of platinum compounds, it derives from the irreversible degeneration of hair cells of the ear. Genetic association studies have suggested an association between GSTP1 c.313A>G variant and platinum-induced ototoxicity in childhood cancer survivors. We aimed to detect the frequency of ototoxicity and associated risk factors in survivors of childhood cancer receiving platinum-based chemotherapy and to detect the relation between GSTP1 c.313A>G (rs1695) polymorphisms and ototoxicity. We conducted a cross-sectional study on 64 cancer survivors who received platinum agents (cisplatin and/or carboplatin) at least 2 years after the end of chemotherapy. The patients underwent comprehensive audiological evaluations and genotyping to detect the presence of the GSTP1 c.313A>G polymorphisms. Hearing loss (HL) was identified in 16/64 patients (25%), including 62.5% treated with cisplatin and 37.5% treated with carboplatin. The greater incidence of ototoxicity was found in children treated for osteosarcoma (28.1%) followed by patients with germ cell tumors (25%) and neuroblastoma (21.9%). The AA, AG, and GG types of GSTP1 c.313A>G variant were detected in 84.4%, 9.4%, and 6.3%, respectively, of patients with HL with a significant association between mutant genotype of GSTP1 rs1695 and platinum-induced ototoxicity (P = .035). HL was not significantly associated with the total cumulative dose of cisplatin and carboplatin. GSTP1 c.313A>G variant may increase the risk of HL in pediatric oncology patients treated with cisplatin or carboplatin chemotherapy. Abbreviations: EDTA = ethylene diamine tetra acetic acid, GCT = germ cell tumor, GST = glutathione-S-transferases, HL = hearing loss, PCR = polymerase chain reaction.
... Anywhere from 20% to 70% of patients experience CDDP-related ototoxicity, with this effect being more prominent in children [167,168]. CDDP induces ototoxicity through induction of ROS and apoptotic cell death within the hair cells of the ear [169,170]. As a result, 40-80% of patients develop permanent hearing loss [171]. ...
Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER-stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.
... Based on this, it is possible that liposomal CDDP (LIPO) may reduce serious side effects such as ototoxicity during neuroblastoma treatment. 11,12 In this study, we established an in vivo neuroblastoma tumor model to determine the effects of CDDP and LIPO in neuroblastoma treatment and side effects like ototoxicity. Tumor development and ototoxicity were examined at both tissue level and functional level. ...
Background:
This study aimed to compare the cytotoxic, cytostatic, and ototoxic effects of lipoplatin compared to cisplatin application in the subcutaneous xenograft nude mouse neuroblastoma tumor model.
Methods:
In this study, C1300 neuroblastoma cells were administered subcutaneously to 21 male nude mice. When the tumor reached 150 mm3 diameter, mice were randomized into 3 groups. Saline, cisplatin, and lipoplatin were given intraperitoneally. The auditory function tests were performed before administration and 72 hours after administration. Mice were sacrificed and the tumor and cochlea were removed after 72 hours. Histopathologic evaluation of necrosis and apoptosis was determined by the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method. Cyclooxygenase 2, superoxide dismutase 2, and inducible nitric oxide synthase levels were determined by immunohistochemistry in tissue samples.
Results:
Apoptosis and necrosis rates were higher in lipoplatin group than in cisplatin group (P=.035 and P=.010, respectively) in tumor tissue. In the spiral ganglion, apoptosis and necrosis were lower in the lipoplatin group than in cisplatin group (P=.002 and P=.002, respectively). Cyclooxygenase 2 pattern in the cochlea was positive in both control and lipoplatin group and negative in cisplatin group (P=.001). Superoxide dismutase 2 and inducible nitric oxide synthase 2 protein expressions showed no difference between groups. The auditory functions were similar to baseline values and had a better threshold value in lipoplatin group than cisplatin group.
Conclusion:
For the treatment of neuroblastoma, the use of lipoplatin seems to be beneficial in reducing side effects of cisplatin. We recommend that the mechanism of these properties of lipoplatin should be evaluated in further studies.
... ROS cause inflammation and apoptosis, especially in the outer hair cells, stria vascularis, and spiral ganglion cells [10,11]. Up to 70% of platinum-treated children develop irreversible hearing loss and eventually 40% of them even need hearing aids at an early stage [12][13][14]. During cancer treatment aminoglycosides, glycopeptides, and diuretics are often prescribed as supportive care therapy [15][16][17][18], but knowledge is lacking on their contribution to hearing loss development in pediatric patients. ...
Background:
Some children with central nervous system (CNS) and solid tumors are at risk to develop ototoxicity during treatment. Up to now, several risk factors have been identified that may contribute to ototoxicity, such as platinum derivates, cranial irradiation, and brain surgery. Comedication, like antibiotics and diuretics, is known to enhance ototoxicity, but their independent influence has not been investigated in childhood cancer patients. Recommendations for hearing loss screening are missing or vary highly across treatment protocols. Additionally, adherence to existing screening guidelines is not always optimal. Currently, knowledge is lacking on the prevalence of ototoxicity.
Objective:
The aim of the Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer (SOUND) is to determine the feasibility of audiological testing and to determine the prevalence and determinants of ototoxicity during treatment for childhood cancer in a national cohort of patients with solid and CNS tumors.
Methods:
The SOUND study is a prospective cohort study in the national childhood cancer center in the Netherlands. The study aims to include all children aged 0 to 19 years with a newly diagnosed CNS or solid tumor. Part of these patients will get audiological examination as part of their standard of care (stratum 1). Patients in which audiological examination is not the standard of care will be invited for inclusion in stratum 2. Age-dependent audiological assessments will be pursued before the start of treatment and within 3 months after the end of treatment. Apart from hearing loss, we will investigate the feasibility to screen patients for tinnitus and vertigo prevalence after cancer treatment. This study will also determine the independent contribution of antibiotics and diuretics on ototoxicity.
Results:
This study was approved by the Medical Research Ethics Committee Utrecht (Identifier 20-417/M). Currently, we are in the process of recruitment for this study.
Conclusions:
The SOUND study will raise awareness about the presence of ototoxicity during the treatment of children with CNS or solid tumors. It will give insight into the prevalence and independent clinical and cotreatment-related determinants of ototoxicity. This is important for the identification of future high-risk patients. Thereby, the study will provide a basis for the selection of patients who will benefit from innovative otoprotective intervention trials during childhood cancer treatment that are currently being prepared.
Trial registration:
Netherlands Trial Register NL8881; https://www.trialregister.nl/trial/8881.
International registered report identifier (irrid):
DERR1-10.2196/34297.
... Based on this, it is possible that liposomal CDDP (LIPO) may reduce serious side effects such as ototoxicity during neuroblastoma treatment. 11,12 In this study, we established an in vivo neuroblastoma tumor model to determine the effects of CDDP and LIPO in neuroblastoma treatment and side effects like ototoxicity. Tumor development and ototoxicity were examined at both tissue level and functional level. ...
Objective: High-dose cisplatin (CDDP) causes dose-limiting side effects in neuroblastoma (NB) treatment. Mesenchymal stem cells (MSC) are a current research area. The aim of this study is to assess the interaction of MSC with CDDP in nude mouse NB model. Methods: Athymic male nude mice (n=28) thatbhad basal auditory tests, with subcutaneous NB were randomized to control, CDDP, MSC and CDDP+MSC treatment groups. Seven days later, hearing tests were repeatedand the animals were sacrificed. Necrosis, apoptosis and viabilitywere assessed in tumors. MSC rate within the tumor was assessed with flow cytometry for triple CD34+ CD44+ and CD117- expression. Expression of the cochlear cell proteins of calretinin, math-1 and myosin2A were immunohistochemically assessed. Results: Tumor tissues were found to have statistically significantly higher levels of necrosis in CDDP and CDDP+MSC groups. MSC did not change the tumor dimensions in the CDDP group. MSC group had higher triple CD34+ CD44+ and CD117- expression within tumor tissue compared to the control and CDDP groups. In the inner ear, the expression of cochlear cell proteins calretinin, math-1 and myosin2A were identified to be highest in MSC group. 15-decibel loss at 12, 16, 20 and 32 kHz frequencies with CDDP was resolved with MSC administration. Conclusion: MSC prevented hearing loss caused by CDDP without disrupting the antitumor effect of CDDP. Systemic MSC may be assessed for clinical use to reduce the side effects of CDDP.
... Risks of cisplatin ototoxicity have been associated with age. Pediatric patients, especially children less than 5 years old, seem to be highly susceptible (Kushner et al., 2006). Male children may be more susceptible than females (Yancey et al., 2012). ...
This chapter presents current information on various types of sensorineural hearing loss (SNHL). SNHL represents the second most common sensory disorder in humans, affecting nearly half a billion persons in the world. This affliction can cause major disabilities, particularly in children. SNHL results from damage to cells in the inner ear. The loss of sensory cells in the cochlea is permanent—they cannot regenerate. The various types of SNHL are presented as a brief overview. A more detailed presentation of SNHL from environmental causes includes a review of noise-induced SNHL and environmental toxins comprising heavy metals. A detailed summary of SNHL caused by ototoxic drugs is presented. The two major classes of ototoxic drugs include the chemotherapeutic agent cisplatin and the aminoglycoside antibiotics. These drugs are used to treat cancer patients and individuals with life-threatening infections, respectively. Results of both animal and human publications are presented. Exciting new investigations of putative protecting agents offer promising approaches to these challenging disorders. Obstacles to the treatment of SNHL include the presence of a barrier system in the inner ear called the blood-labyrinth barrier. This barrier system restricts the access of systemically administered drugs to the cochlea. Novel methods to address these challenges are summarized. These could lead to effective treatments to prevent or reverse SNHL in patients.
... 8,[10][11][12] In addition, hearing loss seems more prevalent in children who are younger at the time of cancer diagnosis compared with older children (see Supporting Table 1). 11,[13][14][15][16][17][18][19][20] To date, however, investigations into whether patterns of CIHL over time are affected by age have been limited. ...
Background
Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin‐induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL.
Methods
Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan‐Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy.
Results
In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%‐84%), with a rapid increase observed to 27% (95% CI, 21%‐35%) at 3 months and to 61% (95% CI, 53%‐69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%‐62%; P < .001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m² increase: hazard ratio [HR], 1.20; 95% CI, 1.01‐1.41) vincristine (HR, 2.87; 95% CI, 1.89‐4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17‐2.95) further influenced CIHL development over time.
Conclusions
In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co‐)medication. These results highlight the need for audiological monitoring at each cisplatin cycle.
... Carboplatin, which is now widely used in childhood cancer, is less ototoxic (its main toxicity is to bone marrow), but it cannot be substituted for cisplatin without careful clinical trial evidence that it is as effective. When used in combination with cisplatin, the combined ototoxicity is greater than the sum of the two individual drugs [13]. When carboplatin is used at high dose, such as for bone marrow ablation prior to autologous bone marrow transplantation, it is ototoxic. ...
Cisplatin is a highly effective chemotherapy medicine used in the treatment of many childhood cancers. Like all medications, cisplatin has many side effects and as always the treatment of cancer in children is a balance between the risks of the medications used and their potential benefits. While many side effects of cisplatin chemotherapy are reversible, one major side effect is permanent and irreversible hearing loss (ototoxicity) in both ears which may worsen with time. The severity of cisplatin-related ototoxicity is associated with age and the cumulative dose received: the younger the child and the higher the total dose, the more severe the hearing loss may be. The spectrum of hearing loss varies from mild to moderate high tone hearing loss, to profound loss across the hearing range and permanent deafness. In addition to hearing loss, some children, especially adolescents, also experience tinnitus and vertigo. Cisplatin ototoxicity is one of most important of the many long-term effects experienced by children who are cured of their cancer. The burden of this toxicity may be compounded by other long-term health issues that emerge with time. This chapter will focus on cisplatin-induced hearing loss, its mechanisms, its health impact on the young person and ways to mitigate or reduce the severity of ototoxicity. This chapter has been written by a multi-disciplinary team including paediatric oncologists, audiologists, a psychologist, a health scientist and a parent of a child growing up with high frequency hearing loss.
... Based on this, it is possible that liposomal CDDP (LIPO) may reduce serious side effects such as ototoxicity during neuroblastoma treatment. 11,12 In this study, we established an in vivo neuroblastoma tumor model to determine the effects of CDDP and LIPO in neuroblastoma treatment and side effects like ototoxicity. Tumor development and ototoxicity were examined at both tissue level and functional level. ...
... 5 Children generally show greater vulnerability to cisplatin-mediated hearing loss than adults. [8][9][10] As hearing loss has recently been ranked fourth leading cause of years lived with disability, 11 while also being an established risk factor for dementia, 12 understanding the mechanisms underlying cisplatin-mediated ototoxicity is of major health relevance and of great need for the prevention and treatment of hearing loss. ...
The chemotherapeutic agent cisplatin is renowned for its ototoxic effects. While hair cells in the cochlea are established targets of cisplatin, less is known regarding the afferent synapse, which is an essential component in the faithful temporal transmission of sound. The glutamate aspartate transporter (GLAST) shields the auditory synapse from excessive glutamate release, and its loss of function increases the vulnerability to noise, salicylate, and aminoglycosides. Until now, the involvement of GLAST in cisplatin‐mediated ototoxicity remains unknown. Here, we test in mice lacking GLAST the effects of a low‐dose cisplatin known not to cause any detectable change in hearing thresholds. When administered at nighttime, a mild hearing loss in GLAST KO mice was found but not at daytime, revealing a potential circadian regulation of the vulnerability to cisplatin‐mediated ototoxicity. We show that the auditory synapse of GLAST KO mice is more vulnerable to cisplatin administration during the active phase (nighttime) when compared to WT mice and treatment during the inactive phase (daytime). This effect was not related to the abundance of platinum compounds in the cochlea, rather cisplatin had a dose‐dependent impact on cochlear clock rhythms only after treatment at nighttime suggesting that cisplatin can modulate the molecular clock. Our findings suggest that the current protocols of cisplatin administration in humans during daytime may cause a yet undetectable damage to the auditory synapse, more so in already damaged ears, and severely impact auditory sensitivity in cancer survivors.
... Unfortunately, in our case no previous pure-tone audiometry tests were performed, which makes it impossible to determine whether the hearing loss is progressive or whether it has remained at the same level since the end of chemotherapy. In the literature, reports are stating that after the completion of treating hearing loss is permanent and stable (19,23). However, many authors have observed progressive hearing loss following chemotherapy with platinum compounds in children treated for solid tumors (15,21,22). ...
Melanotic neuroectodermal tumor of infancy (MNTI) is a rare infantile tumor that originates from mesenchymal-neuroectodermal cells, the treatment of which uses platinum derivatives that can affect hearing loss. The present study evaluated the long-term effects of ototoxicity following chemotherapy with cisplatin, vincristine, cyclophosphamide, teniposide and adriamycin in a 10-year-old patient after surgical removal of a MNTI tumor at the age of 8 months. Audiometric tests (high-frequency tonal audiometry, speech audiometry, speech acoustics, tympanometry and absorbance measurements) were performed during a 10-year follow-up after receiving chemotherapy. Hearing disorders in the high-frequency range (6,000 to 16,000 Hz range) were demonstrated for both ears, indicating that these may be the long-term effects of chemotherapy with use of platinum compounds during the treatment of infants.
... Such an approach allows us to gain deeper insights into the complex mechanism of the acquired resistance, which is a frequent issue specific for high-risk Nbl. This phenomenon worsens the prognosis of Nbl patients resulting in poor outcomes of therapeutic protocols [33][34][35][36][37]. Thus, the description of molecular pathways responsible for CDDP chemoresistance could result in the development of novel therapeutic strategies. ...
The efficiency of cisplatin (CDDP) is significantly hindered by the development of resistance during the treatment course. To gain a detailed understanding of the molecular mechanisms underlying the development of cisplatin resistance, we comparatively analyzed established a CDDP-resistant neuroblastoma cell line (UKF-NB-4CDDP) and its susceptible parental cells (UKF-NB-4). We verified increased chemoresistance of UKF-NB-4CDDP cells by analyzing the viability, induction of apoptosis and clonal efficiency. To shed more light on this phenomenon, we employed custom cDNA microarray (containing 2234 probes) to perform parallel transcriptomic profiling of RNA and identified that 139 genes were significantly up-regulated due to CDDP chemoresistance. The analyses of molecular pathways indicated that the top up-regulation scoring functions were response to stress, abiotic stimulus, regulation of metabolic process, apoptotic processes, regulation of cell proliferation, DNA repair or regulation of catalytic activity, which was also evidenced by analysis of molecular functions revealing up-regulation of genes encoding several proteins with a wide-spectrum of enzymatic activities. Functional analysis using lysosomotropic agents chloroquine and bafilomycin A1 validated their potential to re-sensitize UKF-NB-4CDDP cells to CDDP. Taken together, the identification of alterations in specific genes and pathways that contribute to CDDP chemoresistance may potentially lead to a renewed interest in the development of novel rational therapeutics and prognostic biomarkers for the management of CDDP-resistant neuroblastoma.
... 38 Several investigations evaluated the combined effect of carboplatin with cisplatin in childhood cancer patients. 28,40,62,81 Landier and colleagues 38 evaluated ototoxicity in the setting of young children treated for high-risk neuroblastoma (n=333) and showed in a multivariable analysis a more than threetimes the risk for severe hearing loss among children who had received cisplatin and myeloablative doses of carboplatin compared with those who received cisplatin alone. Similar results were also reported by Parsons and colleagues 40 and Punnett and colleagues 63 in children with neuro blastoma. ...
Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems—such as speech and language, social–emotional development, and learning difficulties—for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.
... It is worth noting that many users did not share the duration of their tinnitus. Further research is needed to identify possible risk factors of permanent tinnitus, although it is known that tinnitus caused by chemotherapy is associated with age and a higher accumulative dose [5,[38][39][40][41]. Users did not commonly report their age or dose of treatment, therefore it would be difficult to conclude if this population reflects previous studies. ...
Background:
Many cancer patients and survivors experience permanent and life-debilitating effects, such as ototoxicity, from treatment. Ototoxicity manifests as high-frequency hearing loss and tinnitus, which can have a detrimental effect on the quality of life (QoL) of those affected. Currently, there is little information and support offered to these patients who experience ototoxicity, potentially leading to many being undiagnosed and untreated.
Objective:
The aim of this study was to explore the extent of ototoxic side effects, such as hearing loss and tinnitus, and their impact on cancer patients following chemotherapy treatment. Secondary objectives included detecting the time periods of onset and duration of the ototoxicity and identifying what support was available to this population.
Methods:
Posts from publicly available online forums were thematically analyzed using the guidelines by Braun and Clarke. A coding manual was iteratively developed to create a framework for the analysis of the ototoxicity experience among the cancer population.
Results:
A total of 9 relevant online forums were identified, consisting of 86 threads and 570 posts from 377 members. Following the bottom-up thematic analysis, 6 major themes were identified: nature of ototoxicity, time of experienced ototoxicity, information on ototoxicity, quality of life, therapies, and online social support.
Conclusions:
There was a significant number of reports expressing concerns about the lack of information on the risk of ototoxicity. More support for those suffering is needed; for example, improved interdepartmental communication between oncology and audiology services could optimize patient care. Patients should also be encouraged to communicate with their health care professionals about their ototoxicity and relay how their QoL is impacted by ototoxicity when accessing support. Tinnitus was the most common concern and was associated with distress. Hearing loss was less common; however, it was associated with fear and employment issues. Those who reported preexisting conditions were fearful about worsening their condition as their QoL was already impacted.
... По мере того, как остальные побочные эффекты препарата постепенно удается взять под контроль, проблема необратимой тугоухости после использования цисплатина остается нерешенной. Его применение вызывает в ряде случаев глубокую двустороннюю сенсоневральную потерю слуха преимущественно в высокочастотном диапазоне у 10-25% взрослых, получающих малые и средние дозы, 50% взрослых, получающих высокие дозы (> 400 мг/м 2 ), и 41-61% детей [4][5][6][7][8]. У детей ототоксичность цисплатина является серьезной проблемой, поскольку даже умеренная потеря слуха может существенно влиять на развитие речи и когнитивных навыков. ...
Cisplatin and its derivatives are widely used chemotherapeutic agents for the treatment of many cancers, including hepatoblas-toma, brain tumors, and germ-cell tumors. This therapy contributed to the dramatic increase in the survival rate. However, its use is restricted by the high incidence of irreversible ototoxicity associated with cisplatin application (in more than 60% of the children receiving it). Some studies have reported that genetic variants of TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) are conferring increased risk of developing cisplatin-induced hearing loss. However, in other studies the results were not replicated. In the present study, we replicated the previous studies based on an independent cohort of Russian patients. SNP genotypes for rs 12201199, rs4646316 and rs 1051640 were determined in DNA samples obtained from 16 patients who developed hearing loss and a group of 34 patients whose hearing was retained. The association between TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) variants and the hearing loss was not observed in our cohort.
Ototoxicity is a devastating direct, irreversible side effect of platinum use in children with cancer, with its consequent effect on speech, language and social development, quality of life and adult productivity. Cisplatin, an essential chemotherapeutic agent for the treatment of solid tumors in children, is a DNA cross-linking agent. Which causes hearing loss in 50-70% of cisplatin treated children. Fortunately, to prevent hearing loss, sodium thiosulfate (STS), which binds to cisplatin, and reduces the superoxides in both tumor and outer hair cells of the cochlea has now been discovered to be an effective and safe otoprotectant if administered correctly. The aim of this perspective paper is to explore the key safety issues and challenges important for pediatric oncologists and pharmacists when considering the clinical use of STS as an otoprotectant for children and adolescents receiving cisplatin. These include: the choice of the formulation; the timing, both that of the STS in relation to cisplatin as well as the timing of the cisplatin infusion itself; the dosing; the challenge left by the definition of localized versus disseminated disease and the difference in indication for STS, between cisplatin treated patients and those receiving another platinum chemotherapeutic agent, carboplatin.
Objective
Intratympanic injections are a safe, well tolerated procedure routinely performed by ENT's specialists. Intratympanic injections of gels have the potential to deliver therapeutics into the cochlea through the round window membrane prolonging the release of drugs in the inner ear compartment. Aim of the present review is to summarize clinical trials testing pharmacological treatments for inner ear pathologies through intratympanic gel formulations.
Data Sources
Online databases (Google scholar and PubMed) and registers ( Clinicaltrials.gov and Euclinicaltrial) were used to identify clinical trials performed between 1990 and 2022.
Review Methods
PRISMA criteria have been followed. Clinical trials testing gel formulations administered through local intratympanic injections and targeting inner ear disorders were included. All the reports were identified by the authors working in pairs sequentially selecting only studies respecting the inclusion criteria.
Results
A total of 45 clinical studies have been noticed; the gels for intratympanic injection are in the form of poloxamers or hyaluronic acid combinations; the trials found target different kind of inner ear disorders: acquired‐stable SNHL, tinnitus, acute sudden SNHL, Meniere disease, cisplatin induced ototoxicity and hearing preservation in patients undergoing cochlear implant surgery.
Conclusion
Few studies listed do not provide the specific kind of gel formulation used but only report the intratympanic delivery vehicle as “gel” or “thermogel”. Multiple clinical studies have been targeting several forms of inner ear disorders by injecting different compounds through poloxamer and hyaluronic acid formulations. Larger and more advanced clinical stages are necessary to confirm the efficacy of these chemical compounds.
The impact of the temporal sequence by which cranial radiotherapy (CRT) and platin‐based chemotherapy (PCth) are administered on sensorineural hearing loss (SNHL) in pediatric and adolescent central nervous system (CNS) and head‐and‐neck (HN) cancer patients has not yet been studied in detail. We examined the ototoxic effects of sequentially applied CRT and PCth. This study included children and adolescents with CNS and HN tumors who participated in the multicountry PanCareLIFE (PCL) consortium. Audiological outcomes were compared between patients who received CRT prior to PCth and those who received it afterwards. The incidence, degree and posttreatment progression of SNHL, defined as Muenster classification grade ≥MS2b, were evaluated in 141 patients. One hundred and nineteen patients were included in a time‐to‐onset analysis. Eighty‐eight patients received CRT prior to PCth (Group 1) and 53 patients received PCth before CRT (Group 2). Over a median follow‐up time of 1.6 years, 72.7% of patients in Group 1 experienced SNHL ≥ MS2b compared to 33.9% in Group 2 (P < .01). A time‐to‐onset analysis was performed for 74 patients from Group 1 and 45 patients from Group 2. Median time to hearing loss (HL) ≥ MS2b was 1.2 years in Group 1 and 4.4 years in Group 2 (P < .01). Thus, audiological outcomes were better for patients who received CRT after PCth than before. This finding should be further evaluated and considered within clinical practice in order to minimize hearing loss in children and adolescents with CNS and HN tumors.
Introduction: Etoposide is a broad-spectrum antitumor drug that has been extensively studied in clinical trials. However, limited information is available regarding its real-world adverse reactions. Therefore, this study aimed to assess and evaluate etoposide-related adverse events in a real-world setting by using data mining method on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.
Methods: Through the analysis of 16,134,686 reports in the FAERS database, a total of 9,892 reports of etoposide-related adverse drug events (ADEs) were identified. To determine the significance of these ADEs, various disproportionality analysis algorithms were applied, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms.
Results: As a result, 478 significant disproportionality preferred terms (PTs) that were identified by all four algorithms were retained. These PTs included commonly reported adverse events such as thrombocytopenia, leukopenia, anemia, stomatitis, and pneumonitis, which align with those documented in the drug’s instructions and previous clinical trials. However, our analysis also uncovered unexpected and significant ADEs, including thrombotic microangiopathy, ototoxicity, second primary malignancy, nephropathy toxic, and ovarian failure. Furthermore, we examined the time-to-onset (TTO) of these ADEs using the Weibull distribution test and found that the median TTO for etoposide-associated ADEs was 10 days (interquartile range [IQR] 2–32 days). The majority of cases occurred within the first month (73.8%) after etoposide administration. Additionally, our analysis revealed specific high-risk signals for males, such as pneumonia and cardiac infarction, while females showed signals for drug resistance and ototoxicity.
Discussion: These findings provide valuable insight into the occurrence of ADEs following etoposide initiation, which can potentially support clinical monitoring and risk identification efforts.
Carbon compounds are all around us; from DNA to CO2, more than a million, billion, or trillion molecules, organic and inorganic, are made of carbon. Elemental carbon has been known and used by men from ancient times. Graphite, diamond, and coal had been the familiar forms of carbon until the last 40 years, when new carbon structures were discovered. In 1996, the Nobel Prize in Chemistry was awarded to Robert F. Curl Jr., Sir Harold Kroto and Richard E. Smalley for the discovery of fullerenes, a new form of elemental carbon. Their experiments were conducted in 1985 [1]. A second Nobel Prize related to new carbon structures was awarded to Andre Geim and Konstantin Novoselov in 2010 for their groundbreaking experiments regarding the two-dimensional new carbon material, gra- phene. Another interesting carbon form are carbon nanotubes which are tubular structures created by rolling-up graphene sheets. They were first synthesized by Sumio Iijima in 1991 [2]. These discoveries are examples that carbon has surprised scientists in the last 35 years and more surprises are yet to come. This chapter will discuss the properties, classification, synthesis methods, purification, and characterization of carbon nanotubes.
Pediatric cancers are relatively rare diseases when considering all types of cancer. Platinum-based chemotherapeutic agents are potent agents against a variety of pediatric malignancies. An important adverse effect of platinum-based agents is the occurrence of hearing loss. This hearing loss can pose a challenge to detect especially if the child is in his early of life. It will also significantly affect the child development of social, pedagogical, and personal dimensions. It is integral to identify incidence of platinum-based ototoxicity and risk factors that increase the likelihood of developing hearing loss in cancer children. We performed a retrospective chart review of 123 pediatric patients who had completed cisplatin and carboplatin therapy for a variety of malignancies. Patients were diagnosed at Princess Nourah Oncology Centre between January 2011 and December 2016, were less than 14 years old at diagnosis. Audiograms were scored using the International Society of Pediatric Oncology (SIOP) Boston Scale (0–4), a validated grading system for cisplatin-related hearing loss. Ototoxicity was reported in 16 patients out of 123 with a rate of 13%. The incidence of ototoxicity was highest in CNS tumors such as medulloblastoma (37.5%) and optic glioma (25%). Males were at greater risk for developing hearing loss than females. Cumulative cisplatin dose and addition radiation therapy were also identified as risk factors for development of ototoxicity (P = 0.008). Nature and location of cancer, gender, cumulative dose, and addition of radiation therapy are important clinical biomarkers of cisplatin ototoxicity.
Platinum-based chemotherapeutic agents cisplatin and carboplatin are widely used in cancer treatment worldwide and may result in ototoxic hearing loss. The high incidence of cancer and salient ototoxic effects of platinum-based compounds pose a global public health threat. The purpose of this study was twofold. First, to estimate the prevalence of ototoxic hearing loss associated with treatment with cisplatin and/or carboplatin via a systematic review and meta-analysis. Second, to estimate the annual global burden of ototoxic hearing loss associated with exposure to cisplatin and/or carboplatin. For the systematic review, three databases were searched (Ovid Medline, Ovid Embase, and Web of Science Core Collection) and studies that reported prevalence of objectively measured ototoxic hearing loss in cancer patients were included. A random effects meta-analysis determined pooled prevalence (95% confidence intervals [CI]) of ototoxic hearing loss overall, and estimates were stratified by treatment and patient attributes. Estimates of ototoxic hearing loss burden were created with published global estimates of incident cancers often treated with platinum-based compounds and cancer-specific treatment rates. Eighty-seven records (n = 5077 individuals) were included in the meta-analysis. Pooled prevalence of ototoxic hearing loss associated with cisplatin and/or carboplatin exposure was 43.17% [CI 37.93-48.56%]. Prevalence estimates were higher for regimens involving cisplatin (cisplatin only: 49.21% [CI 42.62-55.82%]; cisplatin & carboplatin: 56.05% [CI 45.12-66.43%]) versus carboplatin only (13.47% [CI 8.68-20.32%]). Our crude estimates of burden indicated approximately one million individuals worldwide are likely exposed to cisplatin and/or carboplatin, which would result in almost half a million cases of hearing loss per year, globally. There is an urgent need to reduce impacts of ototoxicity in cancer patients. This can be partially achieved by implementing existing strategies focused on primary, secondary, and tertiary hearing loss prevention. Primary ototoxicity prevention via otoprotectants should be a research and policy priority.
Approximately half of the patients diagnosed with neuroblastoma are classified as having high-risk disease. This group continues to have inadequate cure rates despite multiagent chemotherapy, surgery, high-dose chemotherapy with autologous stem cell rescue, and immunotherapy directed against GD2. We review current efforts to try to improve outcomes in patients with newly diagnosed disease by integrating novel targeted therapies earlier in the course of the disease. We further examine a growing list of options available for patients with relapsed or refractory high-risk disease, with an eye toward graduating successful strategies from a relapsed/refractory setting to the frontline setting. Last, we review efforts to study and potentially mitigate the array of late effects faced by survivors of high-risk neuroblastoma.
Lay Summary
Platinum‐containing chemotherapy is often used to treat children with cancer.
Although it is a very effective medication, unfortunately, it causes permanent hearing loss in more than one‐half of the children who receive it.
In this issue of Cancer, an article by Meijer and colleagues shows that very young children are affected early on in their treatment and suggests that the younger the child the more frequently their hearing should be tested during treatment.
This proposal is a real challenge for oncology centers and families practically, emotionally, and socioeconomically.
The findings are provocative but equally stimulating and encouraging; hopefully, they will lead to a new standard of multidisciplinary care for children receiving platinum chemotherapy.
Introduction
Platinum-based chemotherapeutics play an important role in the treatment of cancer at different levels and are the most cited ototoxic agents when scientific evidence is analyzed.
Objective
To present scientific evidence based on a systematic literature review, PRISMA, in order to systematize information on the ototoxic effects of using antineoplastic drugs.
Methods
For the selection of studies, the combination based on the Medical Subject Heading Terms (MeSH) was used. The Medline (Pubmed), LILACS, SciELO, SCOPUS, WEB OF SCIENCE and BIREME databases were used, without restriction of language, period, and location. Evaluation of the quality of the articles was carried out, which included articles with a minimum score of 6 in the modified scale of the literature. The designs of the selected studies were descriptive, cohort, and cross-sectional, which were related to the research objective.
Results
Three articles were included in this systematic review. The ototoxicity caused by cisplatin alone varied from 45% to 83.3%, while that caused by the use associated with carboplatin varied from 16.6% to 75%. There was a significant variation in the cumulative doses of these antineoplastic agents, both in isolated and in combination. Auditory changes, especially at high frequencies, were evident after completion of treatment.
Conclusion
Auditory changes after the use of platinum-based antineoplastic drugs were found, however, there was an important heterogeneity regarding the frequency of ototoxicity and the cumulative dose of the drugs used.
Deafness is the most common sensory disorder in the world. Ototoxic drugs are common inducing factors of sensorineural hearing loss, and cochlear hair cell (HC) damage is the main concern of the present studies. Cisplatin is a widely used, highly effective antitumor drug, but some patients have experienced irreversible hearing loss as a result of its application. This hearing loss is closely related to HC apoptosis and autophagy. U0126 is a specific inhibitor of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathway and has neuroprotective effects. For example, the neuroprotective effect of U0126 on ischemic stroke has been widely recognized. In neural cells, U0126 can prevent death due to excess glutamate, dopamine, or zinc ions. However, no studies of U0126 and ototoxic drug-induced injury have been reported to date. In the present study, we found that U0126 pretreatment significantly reduced the apoptosis and autophagy of HCs in auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear HCs. In addition, U0126 reduced the cisplatin-induced production of reactive oxygen species as well as the cisplatin-induced decrease in the mitochondrial membrane potential. These findings suggest that U0126 may be a potential therapeutic candidate for the prevention of cisplatin-induced ototoxicity.
Primary central nervous system (CNS) tumours account for about 24% of childhood cancers, thereby presenting the most frequent solid tumours and second most frequent malignancies in childhood and adolescence [1, 2]. More than 400 children and adolescents are diagnosed with a CNS tumour in Germany each year. About 95% of them are treated according to prospective, multi-centre therapy optimisation studies or non-interventional registries, respectively, conducted by the German Paediatric Brain Tumour Consortium (HIT-Network) and the European branch of the International Society of Paediatric Oncology (SIOP-E). They collaboratively coordinate trials and reference centres for different childhood brain tumour entities, thereby promoting continuous optimisation of treatment concepts with quality-controlled standards for diagnosis, treatment and supportive care.
In 2016, approximately 2400 neuroblastoma patients in Germany had survived ≥10 years after diagnosis. The late sequelae follow-up programs should be tailored based on the highly divergent biology of low-risk and high-risk disease, the related treatment intensities, and the resulting varying risks of developing late effects. This chapter reviews the current knowledge of the most relevant long-term problems for neuroblastoma survivors, focusing on late mortality, reduced quality of life, hearing impairment, thyroid disorders, cardiotoxicity, second malignancies, and altered musculoskeletal health.
Ototoxicity (i.e., toxic damage to the ear) is a side effect of many drugs that are used in cancer treatment, including anticancer drugs and co-medication such as aminoglycoside antibiotics, glycopeptide antibiotics, macrolides, nonsteroidal anti-inflammatory drugs, loop diuretics, ototopical medication, and cranial irradiation, among others. Aminoglycosides and platinum-based chemotherapy agents are of greatest concern as they often lead to permanent ototoxicity. Ototoxic drugs can have severe short- and long-term effects on patients’ hearing and balance systems, such as impaired speech perception, which impedes language development, psychosocial development, educational attainment, employment prospects, and quality of life. Oncology professionals must balance the benefits of any planned drug treatment against these potential effects. Susceptibility to ototoxic effects is defined by genetic and non-genetic risk factors, such as age or other concomitant ototoxic treatment. Various subjective and objective audiological tests can be used to identify ototoxicity in individual patients, such as pure-tone or play audiometry alongside otoacoustic emissions (OAEs) and auditory brainstem response (ABR) testing. The pros and cons of diagnostic audiological practice, treatment options, and current research into otoprotective medication are discussed in this chapter.
Ototoxicity and other neurologic toxicities are potential consequences of exposure to common therapeutic agents used during treatment of childhood cancer, including platinum and vinca alkaloid chemotherapy, cranial radiation, surgery involving structures critical to cochlear and neurologic function, and supportive care medications such as aminoglycoside antibiotics and loop diuretics. This article provides an overview of ototoxicity and other neurologic toxicities related to childhood cancer treatment, discusses the challenges that these toxicities may pose for survivors, and presents an overview of current recommendations for surveillance and clinical management of these potentially life-altering toxicities in survivors of childhood cancers.
With the advent of genome-editing technologies, targeting genome engineering is no longer a hypothetical abstract. As application area of genome-editing tools is extending beyond the limits of research and biomedical remedies, specific ethical apprehensions are prevalent around the global community about the appropriate scope of genome-editing tools to be used. Genome-editing tools, i.e., meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspersed short palindromic repeats (CRISPR/Cas system), accelerate cancer research not only in its base study as well as in its cure by dissecting the mechanism of tumor development, categorizing targets for drug progression, and identifying arm cells for cell-dependent therapies. Current applications of cancer research and cure are discussed in this chapter. Moreover, it has also been discussed that genome editing is the possible cause of enhancing the risk of cancer development.
Clinical manifestations of complex diseases like cancer oblige deep knowledge of each attribute. Both structural and functional aspects of the genome are essential for the characterization of DNA intended for sequencing the whole genome, accompanied with the knowledge of bioinformatics analysis and computational simulation, improving the selection of target biomarkers and drug designing strategies. In this chapter, we have given a brief outline of cancer genomics, sequencing methods (conventional and next-generation), biomarkers, DNA, and tissue microarrays. Recent investigations in different types of cancer demonstrate its relationship with gene mutations which assign the specific chromosome and physical mapping of genome structure using both experimental and computational models. This chapter discusses the cost-effectiveness and labor intensity of techniques utilized for gene manipulations which advance the practices for biomedical and clinical diagnostics strategies. On the other hand, biomarkers are the biological molecules which act as indicators for certain diseases and can be elevated or reduced during certain pathological conditions, consequently revealing the route to the detection, diagnosis, prognosis, and predictions for many disease classifications. Mass-spectrometric analysis of whole protein sequences is also getting attention due to its promising approaches, facilitating diagnosis in the field of infections as well as in the indication of pathological stages, with the help of protein release profiling and expression both qualitatively and quantitatively. DNA microarrays and tissue microarrays are the techniques that have been evolved for the economization of cost and time for both DNA and tissue analysis, respectively, minimizing the laborious procedures for diagnosis. The advantages of these aforementioned techniques continue to progress, thus, mesmerizing the scientific world.
The purpose of this study is to provide the researchers with the bigger academic network for the understanding of the incorporated proof about current pharmacogenomics information on pediatric oncology and hematology. This primary assessment will help and guide the researchers and clinicians by giving a thought about the current situation of research, as far as customizing drug for kids with malignant growth (cancer). This study also describes the gene-drug associations with substantial and adequate power of association put forward by PharmGKB (Pharmacogenomics Knowledgebase). Some drugs with strong pharmacogenetic evidence like thiopurines and some with moderate pharmacogenetic evidence like vincristine are also discussed. Upcoming suggestions to achieve this objective will help to put forward the recommendations. Pharmacogenetic gene-drug link studies, thus, influence the reconsidering of study plans to produce sensible results. Genetic roots of oxidative force reaction or genome stability disturbing reaction were categorized as association with moderate evidence but have not yet been tested in children.
Cancer proteomics is a diverse and challenging field. It provides the promising tool that aids in the understanding of the disease, yet early-stage diagnosis is still a question and crucial for successful treatment of cancer. Genomics aided with proteomics has emerged as a larger platform for understanding the disease spread, proliferation, metastasis, genomic aberrations, mutational changes, therapeutics, design drug delivery system, proteomic anomalies, structural changes, and signaling pathways and moving toward personalized approach. Biomarker identification and development of the panel are very precious in cancer treatment. Generally, biomarker identification, validation, and clinical examination are specific tools for accurate diagnostic, prognostic, and therapeutics. Present-day advances in proteomics and computational sciences have opened a gateway for the identification and quantitative analysis of protein variations associated with the complexities and heterogeneity of tumor development. Concept of personalized medicine is an emerging approach for cancer patient treatment, yet it has many challenges to overcome before its clinical application. Translational research in oncology still needs lots of quality research to overcome many challenges and for improvement in biomedical application and cancer patient care.
Cisplatin is a highly effective antineoplastic agent used to treat solid tumors. Unfortunately, the administration of this drug leads to significant side effects, including ototoxicity, nephrotoxicity, and neurotoxicity. This review addresses the mechanisms of cisplatin-induced ototoxicity and various strategies tested to prevent this distressing adverse effect. The molecular pathways underlying cisplatin ototoxicity are still being investigated. Cisplatin enters targeted cells in the cochlea through the action of several transporters. Once it enters the cochlea, cisplatin is retained for months to years. It can cause DNA damage, inhibit protein synthesis, and generate reactive oxygen species that can lead to inflammation and apoptosis of outer hair cells, resulting in permanent hearing loss. Strategies to prevent cisplatin ototoxicity have utilized antioxidants, transport inhibitors, G-protein receptor agonists, and anti-inflammatory agents. There are no FDA-approved drugs to prevent cisplatin ototoxicity. It is critical that potential protective agents do not interfere with the antitumor efficacy of cisplatin.
Cisplatin is the principal chemotherapeutic agent and also tremendously increases the survival for pediatric patients with neuroblastoma or hepatoblastoma. With the extended overall survival period, clinical medical workers and parents gradually attach more attention to the late effect of chemotherapy of these children. The purpose of this study is to analyze the incidence and risk factors of cisplatin-based hearing loss. We retrospectively collected the archives of cisplatin-based chemotherapy and audiometric evaluation from 2005 through 2017 at Xinhua Hospital. From 384 patients treated with cisplatin, full data of 59 patients were available, and 14 cases (23.7%) were identified as significant hearing loss. The median time from usage of platinum compounds to the most recent audio test was 406 days. Cumulative and single maximum cisplatin dose was 622.6±283.2 and 137.6±51.6 mg/m/cycle, respectively. Accumulated cisplatin dose (95% confidence interval, 1.001-1.006; P=0.012) and single maximum cisplatin dose (95% confidence interval, 1.000-1.029; P=0.049) were independently important predictors for moderate to severe hearing loss in children treated with cisplatin. Cisplatin can cause ototoxicity which profoundly handicap language development and social communication for children. Regular audiological management and long-term follow-up are strongly recommended for this vulnerable group.
From March 1984 through March 1989 we performed 235 audiometric tests on 39 children with malignant brain tumors who were treated with cisplatin 100 mg/m2 every 3 weeks for three courses and vincristine weekly for 9 weeks followed by cranial irradiation. Twenty-eight of the 39 children had sufficient serial testing for evaluation of ototoxicity secondary to cisplatin. Following the third cisplatin treatment (300 mg/m2 cumulative dose), 20% of the assessable children had hearing loss limited to the high frequencies of 6,000 to 8,000 Hz, 16% had hearing loss beginning at 3,000 to 4,000 Hz, and three children (11%) had loss within the speech frequencies beginning at 1,000 to 2,000 Hz. Eighteen of 19 children (95%) who were evaluated comparatively at a median of 15 months following radiation showed no significant change from preradiation testing. There was no correlation between hearing loss and patient age. We conclude that cisplatin ototoxicity was acceptable and that radiation therapy does not increase the ototoxicity of cisplatin when the drug is given before, instead of following, cranial irradiation.
Twenty-two children and adolescents who had received cisplatinum for the treatment of solid tumours underwent audiometry to ascertain the extent of hearing damage. Five patients complained of hearing difficulties, causing difficulty at school in one child. Hearing loss greater than 20 decibels occurred in four patients at 1,000 Hz, seven at 2,000 Hz, 13 at 4,000 Hz and 21 at 8,000 Hz. Median hearing loss was greater at higher frequencies (P less than 0.0001), and with increasing cumulative dose of cisplatinum. However, a 'plateau' phenomenon was observed, with no apparent further deterioration in hearing loss at doses greater than 600 mg m-2. Two children who had received prior aural radiotherapy had severe hearing loss. Severe, mostly asymptomatic, ototoxicity is common in children given cisplatinum. However, there is considerable interpatient variability in the hearing loss suffered.
Children with neuroblastoma receiving high-dose carboplatin as part of their conditioning regimen for autologous marrow transplantation have a high incidence of speech frequency hearing loss. We evaluated hearing loss in 11 children with advanced stage neuroblastoma who underwent autologous marrow transplantation, following a conditioning regimen containing high-dose carboplatin (2g/m2, total dose). Audiometric evaluations were obtained at diagnosis, prior to and following transplant. Exposure to other known ototoxins also was assessed. All patients sustained worsening of hearing following high-dose carboplatin. Nine of the 11 children (82%) had evidence of speech frequency hearing loss post transplant for which hearing aids were recommended (grades 3-4). Three of the nine children had speech frequency loss prior to transplant which progressed following transplant. The entire group was heavily pre-treated with platinum-containing chemotherapy pre-BMT and had extensive exposure to other ototoxins, including aminoglycoside antibiotics, diuretics, and noise exposure - all of which could have exacerbated the effects of carboplatin. High-dose carboplatin is ototoxic, particularly in patients who have been primed with previous platinum therapy or other ototoxic agents. We conclude that further efforts are needed to monitor and minimize this complication. In cases where hearing loss is inevitable due to cumulative ototoxic exposures, families need to be adequately prepared for the tradeoffs of potentially curable therapy.
Topotecan appears to be relatively unaffected by the most common multidrug resistance mechanisms, may potentiate cytotoxicity of alkylators, has good penetration into the central nervous system, is active against a variety of neoplasms, and has myelosuppression as its paramount toxicity. We present our experience with a myeloablative regimen that includes topotecan. Twenty-one patients with poor-prognosis tumors and intact function of key organs received topotecan 2 mg/m2 by 30-min intravenous (i.v.) infusion on days -8, -7, -6, -5, -4; thiotepa 300 mg/m2 by 3 h i.v. infusion on days -8, -7, -6; and carboplatin by 4 h i.v. infusion on days -5, -4, -3 with a daily dose derived from the pediatric Calvert formula, using a targeted area under the curve of seven mg/ml* min ( approximately 500 mg/m2/day). Stem cell rescue was on day 0. The patients were 1 to 29 (median 4) years old; 18 were in complete remission (CR) and three in partial remission (PR). Early toxicities were severe mucositis and erythema with superficial peeling in all patients and a seizure, hypertension, and renal insufficiency followed by veno-occlusive disease in one patient each. Post-transplant treatment included radiotherapy alone (four patients) or plus biological agents (11 patients with neuroblastoma). With a follow-up of 6+ to 32+ (median 11+) months, event-free survivors include 10/11 neuroblastoma patients (first CR), 4/5 brain tumor patients (second PR or CR), 1/3 patients with metastatic Ewing's sarcoma (first or second CR), and a patient transplanted for multiply recurrent immature ovarian teratoma; a patient with desmoplastic small round-cell tumor (second PR) had progressive disease at 8 months. Favorable results for disease control, manageable toxicity, and the antitumor profiles of topotecan, thiotepa, and carboplatin, support use of this three-drug regimen in the treatment of neuroblastoma and brain tumors; applicability to other tumors is still uncertain.
The purpose of this study was to evaluate the severity of hearing loss after cisplatin and/or carboplatin treatment in young children and to analyze its evolution and its relation to different therapy schedules.
One hundred twenty patients treated in the Pediatrics Department at the Institut Gustave-Roussy from 1987 to 1997 for neuroblastoma, osteosarcoma, hepatoblastoma, or germ cell tumors were analyzed. Median age at diagnosis was 2.6 (range 0-17) years. Median follow-up was 7 (1-13) years. Chemotherapy regimens contained cisplatin and/or carboplatin. Three patients also received high-dose carboplatin. Cisplatin was administered at a dose of 200 mg/m/course in 72% of cases. The median cumulative dose was 400 mg/m for cisplatin and 1,600 mg/m for carboplatin. Hearing loss of grade 2 or above, according to Brock's grading scale, was revealed with pure tone audiometry and behavioral techniques.
Carboplatin alone was not ototoxic. Deterioration of hearing of grade 2 or above was observed in 37% of patients treated with cisplatin and 43% of patients treated with cisplatin plus carboplatin (P = NS). Fifteen percent of patients experienced grade 3 or 4 ototoxicity. Ototoxicity was most often observed after a total cisplatin dose of at least 400 mg/m. No improvement was observed with time; on the contrary, worsening or progression of hearing loss at lower frequencies was detected during follow-up. Only 5% of audiograms showed toxicity of at least grade 2 before the end of therapy; in contrast, this level was observed in 11% of early post-therapy evaluations and in 44% after more than 2 years of follow-up.
Children treated with cisplatin at cumulative doses approaching 400 mg/m require long-term surveillance to avoid overlooking hearing deficits. Carboplatin, at a standard dose, does not appear to be a significant risk factor for ototoxicity even in patients who have already been treated with cisplatin.
Carboplatin is less ototoxic than cisplatin, but ototoxicity may occur with carboplatin at higher doses. We evaluated hearing in children with brain tumors treated with conventional dose cisplatin followed by high‐dose carboplatin. Children under 6 years of age, newly diagnosed with brain tumors, were treated after surgery with cisplatin, Etoposide, cyclophosphamide, and vincristine, followed by consolidation with carboplatin, ThioTEPA, Etoposide, and autologous bone marrow rescue. Hearing was assessed before and after consolidation, utilizing standard audiometric techniques. Seven of the 11 evaluable patients developed high‐frequency sensorineural hearing loss after induction therapy. Hearing deteriorated after consolidation in five patients, with pure tone threshold shifts of up to 65 dB between 2,000 and 8,000 Hz. Of these five patients, audiological abnormalities were documented in four prior to consolidation, one received cranial irradiation after consolidation, and all five received aminoglycoside antibiotics for at least 2 weeks, with toxic drug levels in four. Three patients have subsequently required hearing aids. Significant ototoxicity is common in these patients. Ototoxicity related to consolidation therapy is likely due to the high dose of carboplatin used, prior cisplatin therapy, aminoglycosides, and, in one patient, cranial irradiation. Audiological assessment is essential in children treated with dose‐intensive chemotherapy regimens containing cisplatin and carboplatin for identification and rehabilitation of ototoxicity. © 1996 Wiley‐Liss, Inc.
Objectives:
The purpose of this study was to evaluate the severity of hearing loss after cisplatin and/or carboplatin treatment in young children and to analyze its evolution and its relation to different therapy schedules.
Methods:
One hundred twenty patients treated in the Pediatrics Department at the Institut Gustave-Roussy from 1987 to 1997 for neuroblastoma, osteosarcoma, hepatoblastoma, or germ cell tumors were analyzed. Median age at diagnosis was 2.6 (range 0-17) years. Median follow-up was 7 (1-13) years. Chemotherapy regimens contained cisplatin and/or carboplatin. Three patients also received high-dose carboplatin. Cisplatin was administered at a dose of 200 mg/m/course in 72% of cases. The median cumulative dose was 400 mg/m for cisplatin and 1,600 mg/m for carboplatin. Hearing loss of grade 2 or above, according to Brock's grading scale, was revealed with pure tone audiometry and behavioral techniques.
Results:
Carboplatin alone was not ototoxic. Deterioration of hearing of grade 2 or above was observed in 37% of patients treated with cisplatin and 43% of patients treated with cisplatin plus carboplatin (P = NS). Fifteen percent of patients experienced grade 3 or 4 ototoxicity. Ototoxicity was most often observed after a total cisplatin dose of at least 400 mg/m. No improvement was observed with time; on the contrary, worsening or progression of hearing loss at lower frequencies was detected during follow-up. Only 5% of audiograms showed toxicity of at least grade 2 before the end of therapy; in contrast, this level was observed in 11% of early post-therapy evaluations and in 44% after more than 2 years of follow-up.
Conclusions:
Children treated with cisplatin at cumulative doses approaching 400 mg/m require long-term surveillance to avoid overlooking hearing deficits. Carboplatin, at a standard dose, does not appear to be a significant risk factor for ototoxicity even in patients who have already been treated with cisplatin.
Cis-dichlorodiammineplatinum (CDDP) and VM26, both of which have been proven efficient in treating neuroblastoma, were combined in a sequential schedule and administered to 22 children with disseminated neuroblastomas resistant to treatment with cyclophosphamide and doxorubicin (Adriamycin). During this same study, 14 children were prospectively evaluated for the effect of CDDP on magnesium metabolism and the effect of the induced hypomagnesemia on parathyroid function. Complete or partial tumor responses were achieved in six and nine cases, respectively and were of prolonged duration (longer than six months) in eight of the 15 responding. It was also shown that CDDP-induced hypomagnesemia is the result of excessive renal loss and is severe enough to interfere with the normal parathormone response to hypocalcemia.
We evaluated the toxicity and maximum tolerated dose of topotecan in a novel myeloablative regimen as treatment for high-risk pediatric tumors. Patients received an assigned topotecan dosage in combination with fixed doses of carboplatin and thiotepa, followed by autologous hematopoietic stem cells infusion. Topotecan dose was escalated in cohorts of four patients until the maximum tolerated dose of topotecan was defined or until accrual of 30 patients. Pharmacokinetics of topotecan were examined, and event-free survival was estimated. We describe preliminary results following treatment of 25 pediatric patients with high-risk solid tumors. Med. Pediatr. Oncol. 35: 719–723, 2000. © 2000 Wiley-Liss, Inc.
BackgroundA secondary end point of the NBL90 protocol (Rubie H et al. Pediatr Oncol 2001;36:247–250) was the concern in this infant population for possible carboplatin-(CBDCA) induced late side effects including impaired renal and hearing functions.ProcedureGlomerular filtration rate (GFR), tubular function (TF), pure tone audiometry (PTA), high-frequency, and transient evoked-otoacoustic emission were prospectively assessed in 30 children alive and disease-free 6 years after the end of the treatment.ResultsMedian age at diagnosis and at assessment was 4.7 months and 7 years, respectively. Blood pressure was ≤97.5 centile in all children. The mean estimated GFR was 114 ± 13 ml/min/1.73 m2 by Schwartz formula [range 87–145]. TF assessment failed to demonstrate any impairment. 29/30 children had grade 0 ototoxicity and all transient evoked otoacoustic emission were normal.Conclusions
With a 6-year follow-up the combination of VP16 and carboplatin given at conventional doses is safe on renal and hearing functions in infants with unresectable neuroblastomas treated according to SFOP NB90. Pediatr Blood Cancer 2005; 45:32–36. © 2005 Wiley-Liss, Inc.
Objective:
To describe hearing changes in a group of 28 children (age range, 8-180 mo) undergoing protocol-based cisplatin therapy.
Methods:
Conventional, play audiometry, visual reinforcement audiometry (VRA), immittance audiometry, transient click evoked otoacoustic emissions (OAEs), and auditory brainstem response (ABR) evoked potentials were used to assess peripheral sensitivity and for threshold determination.
Results:
Bilateral symmetrical high-frequency sensorineural hearing loss was noted in 9 of the 28 children (26%). Hearing loss was evident as early as 1 month after chemotherapy and as late as 50 months and was not dependent on individual or cumulative dosage of cisplatin.
Conclusions:
1) Presence of sensorineural hearing loss was independent of individual and/or cumulative dosage of cisplatin; 2) audiologic assessment should be incorporated into a child's periodic medical evaluations after chemotherapy treatment, as onset of sensorineural hearing loss cannot be predicted; 3) personal hearing aids may be indicated for those children with hearing loss affecting the low- to mid-frequencies; a personal assistive listening device (frequency modulated system) may be more appropriate for losses above 3000 Hz; and 4) evaluation and intervention by a speech-language pathologist may be indicated to address possible articulation or language development problems consequent to hearing loss.
Carboplatin is less ototoxic than cisplatin, but ototoxicity may occur with carboplatin at higher doses. We evaluated hearing in children with brain tumors treated with conventional dose cisplatin followed by high-dose carboplatin. Children under 6 years of age, newly diagnosed with brain tumors, were treated after surgery with cisplatin, Etoposide, cyclophosphamide, and vincristine, followed by consolidation with carboplatin, ThioTEPA, Etoposide, and autologous bone marrow rescue. Hearing was assessed before and after consolidation, utilizing standard audiometric techniques. Seven of the 11 evaluable patients developed high-frequency sensorineural hearing loss after induction therapy. Hearing deteriorated after consolidation in five patients, with pure tone threshold shifts of up to 65 dB between 2,000 and 8,000 Hz. Of these five patients, audiological abnormalities were documented in four prior to consolidation, one received cranial irradiation after consolidation, and all five received aminoglycoside antibiotics for at least 2 weeks, with toxic drug levels in four. Three patients have subsequently required hearing aids. Significant ototoxicity is common in these patients. Ototoxicity related to consolidation therapy is likely due to the high dose of carboplatin used, prior cisplatin therapy, aminoglycosides, and, in one patient, cranial irradiation. Audiological assessment is essential in children treated with dose-intensive chemotherapy regimens containing cisplatin and carboplatin for identification and rehabilitation of ototoxicity. © 1996 Wiley-Liss, Inc.
BACKGROUND
The authors assessed key effects of granulocyte-colony stimulating factor (G-CSF) used prophylactically with multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy. To the authors' knowledge, no large study has focused on G-CSF in this setting, yet this kind of treatment has recently become standard for poor risk pediatric solid tumors such as neuroblastoma.PATIENTS AND METHODS.Children with neuroblastoma received cyclophosphamide 140 mg/kg (i.e., 4200 mg/m2), doxorubicin 75 mg/m2, and vincristine (CAV) in cycles 1, 2, 4, and 6 and cisplatin 200 mg/m2 and etoposide 600 mg/m2 (P/VP) in cycles 3, 5, and 7. To maximize dose intensity, chemotherapy was begun as soon as the absolute neutrophil count (ANC) was ≥ 500/μL and platelet count was ≥ 100,000/μL. No cytokines were used during 1990–1994 (control group; n = 28), but G-CSF was used from 1995 to 1998 (G-CSF group; n = 30) at 5 μg/kg/day subcutaneously from 1 day after chemotherapy until the ANC was ≥ 500/μL on 2 successive days or was ≥ 1000/μL.RESULTSEach cycle of CAV decreased ANCs to < 200/μL in all 58 patients; recovery to 200/μL and to 500/μL was significantly sooner with G-CSF. In contrast, P/VP did not invariably cause severe neutropenia: similar numbers of patients in each group maintained ANCs ≥ 200/μL and ≥ 500/μL; recovery to 500/μL (but not to 200/μL) was significantly faster in the G-CSF group. G-CSF had no impact on rates of febrile episodes. Bacterial/fungal infections were slightly less frequent in the G-CSF group with CAV (P = 0.11) but not with P/VP. Dose intensity through cycle 4 was the same in both groups. Beginning with cycle 3, G-CSF patients had slower recovery to platelet counts ≥ 100,000/μL. Response rates were similar in the two groups.CONCLUSIONS
With multiple cycles of strongly myelosuppressive alkylator-based combination chemotherapy, prophylactic use of G-CSF hastened ANC recovery but did not reduce the incidence of febrile episodes, had little impact on infection rates, did not yield augmented dose intensity, was associated with prolonged thrombocytopenia, and had no effect on response rates of neuroblastoma. The data support more limited use of G-CSF. Cancer 2000;89:2122–30. © 2000 American Cancer Society.
Unlabelled:
The tolerance to and toxicity of cisplatin treatment was retrospectively studied in 30 infants. A total of 191 courses were given with a median of six per child and a median cumulative dose of 400 mg m-2. Electrolyte disturbances were noted in 15/23 infants (38:144 courses): hypomagnesaemia, which was dose related, in 10/23 (25/144 courses), hyponatraemia in 6/23 (7:144 courses), hypercalcaemia in 4/23 (6/144 courses), and hypocalcaemia in 3/23 (4/144 courses). Seizures occurred in two infants. Vomiting followed 31/191 courses and neutropenic febrile episodes 23/191 courses. Median survival is 6 years 1 month. Six children have died of progressive malignancy. Glomerular filtration rate was less than 80 ml min-1 per 1.73 m2 in 15/29 children, at or within a month of the end of treatment; of ten retested at follow-up, eight had increased to more than 80 ml min-1 per 1.73 m2 (P = 0.027). High-frequency hearing loss was observed in 10/28 children, but was only significant in five (four grade 2 and one grade 3).
In conclusion:
the long-term toxicity of cisplatin in infants, at this dose range and schedule, is no more severe than in older children.
In a high-dose schedule for disseminated neuroblastoma, eight courses of chemotherapy were administered every 10 days, regardless of myelosuppression, to eradicate tumour cells rapidly and reduce emergence of drug-resistant clones. Relatively non-myelotoxic vincristine and cisplatin were alternated with high-dose cisplatin-etoposide and cyclophosphamide-etoposide. Of 12 evaluable patients, there were 1 complete (CR), 3 very good partial (VGPR), 5 partial (PR) and 3 mixed responses (MR) 100 days after starting treatment. 6 out of 9 achieved a bone marrow CR at 40 days. 9 of 11 primary tumours were completely resected, after which 4 patients had CR, 3 VGPR (bone scan alone being abnormal), 4 PR and 1 mixed response (MR). Myelotoxicity was the major adverse effect. The only death was due to fungal infection. Clinically important renal dysfunction occurred in 3 patients. 4 had convulsions and 4 temporary hypertension. This schedule produced a rapid response and its toxicity, though serious, was manageable. Further evaluation is warranted.
Cis-platinum is an ototoxic antineoplastic drug. Evaluation of auditory thresholds in 33 children receiving cis-platinum shows that a threshold shift at 6 and 8 kHz is first measurable after a cumulative dose of 201 to 300 mg/m2. A 35- to 40-dB high-frequency threshold shift is evident after a cumulative cis-platinum dose of 301 to 400 mg/m2. Increasing cumulative doses of cis-platinum are associated with a greater degree of hearing loss. Receiver-operator characteristic curves were used to find a criterion value that effectively identified threshold shifts that were due to cis-platinum ototoxicity. A 15-dB or greater shift in the 6- and 8-kHz threshold average identifies a high true-positive (50%) and low false-positive (0%) rate of cis-platinum-induced hearing loss. Using this criterion, cis-platinum ototoxicity affected 77% of children who received cis-platinum (median cumulative dose 360 mg/m2).
Despite the recognized ototoxicity of cis-platinum, a clinical outline for the audiologic evaluation of patients receiving this drug has not been clearly defined. In a practical approach to this problem, the audiograms of 48 pediatric patients referred for monitoring during planned cis-platinum therapy were reviewed. Eleven patients tested with auditory brain-stem response (ABR) audiometry demonstrated several limitations of this modality. Fourteen children underwent initial ABR testing followed by at least two pure-tone audiograms. The remaining 23 patients had their hearing evaluated by pure-tone audiometry only. Various factors such as patient age, cis-platinum dosage, and cranial radiation exposure were analyzed for apparent effect. Younger patients tended to be more susceptible to audiologic changes with the administration of cis-platinum. The proportion of patients who demonstrated a hearing loss increased with successive dosing as did the severity of the hearing loss. Prior exposure to cranial radiation was strongly linked to the development of hearing loss following cis-platinum therapy. Guidelines are presented regarding the use of clinical audiometry in the screening of these pediatric oncology patients.
A long-term follow-up study was carried out to assess ototoxicity in children who had been treated for a malignant tumour with "standard dose" cisplatin (60-100 mg/m2 per course), and were at least 2 years from stopping treatment. The median age at diagnosis was 2 years 2 months (range 1 month to 13.5 years). On the basis of hearing assessment by pure-tone audiometry, a practical grading system of hearing loss from 0 to 4 is proposed. Moderate to severe high-frequency hearing loss (grade 2-4) was found in half the children and 10 require appropriate hearing aids. The risk of developing ototoxicity increased significantly with the cumulative cisplatin dose (P = 0.027), although there was considerable individual susceptibility. Serial follow-up testing, to a median of 4 years after completion of cisplatin treatment, showed no recovery of hearing in any of these children. We suggest careful monitoring of young children by a consultant audiological physician throughout treatment with cisplatin, particularly when doses of 400 mg/m2 and over have been reached. Alternative chemotherapy should be discussed if grade 2 ototoxicity develops.
Thirty-four children, age 2-19 years, with brain tumors were treated with surgical resection, irradiation, and a cisplatin (CDDP) containing regimen. Audiologic assessments were conducted prior to each cycle of CDDP to monitor the ototoxic effects of CDDP. Twenty-eight patients with posterior fossa (PF) tumors received 5,040 to 5,650 cGy irradiation to the PF and 0-3,600 cGy to the remainder of the craniospinal (CS) axis. Six patients with supratentorial tumors received 5,140-5,580 cGy to the tumor site and 3,600-4,500 Gy to the remainder of the CS axis. Cycles of CDDP (68 mg/m2), lomustine (75 mg/m2), and vincristine (1.5 mg/m2 weekly for 3 weeks) were given every 6 weeks to 30 children immediately following irradiation, and to 4 at relapse. CDDP was infused over 8 h. Significant hearing loss, defined as a greater than 20-dB change from baseline in the hearing level (HL), occurred in the 250- to 2,000-Hz range in 4 of 29 patients receiving a cumulative dose (CD) of 410 mg/m2, and in 14 of 25 patients receiving a CD of 474 mg/m2. At 4,000 Hz, hearing sensitivity progressed from a HL of 20 +/- 2 dB at a CD of 203 mg/m2 to 31 +/- 6 dB (p less than 0.05) at a CD of 474 mg/m2 (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Dose-dependent reduction of auditory function mainly in the high frequency range has been described as a common adverse side effect of cis-platinum. Here we report on a 4-year-old girl with osteosarcoma of the right distal femur who developed acute bilateral deafness 3 days after a single infusion of high-dose cis-platinum (150 mg/m2) during preoperative chemotherapy. Sudden disabling ototoxicity should be considered when administering high-dose cis-platinum to young children.
One hundred seventy-seven children and young adults with various malignant neoplasms were prospectively tested for hearing loss after they had received cisplatin (n = 146), cranial irradiation (n = 18), or both (n = 13). Adequate renal function, no history of treatment with ototoxic drugs other than cisplatin, and availability for repeated audiometric testing were requirements for enrollment. Substantial hearing loss, defined as a hearing threshold of 50 dB or greater, was noted in only 11% of the cohort on tests conducted at the common speech frequencies (500 to 3,000 Hz). About half the patients had substantial deficits at higher frequencies (4,000 to 8,000 Hz). The probability of substantial hearing loss was directly related to the cumulative dose of cisplatin. In nonirradiated patients tested at the speech frequencies, there was a negligible risk of substantial deficits over the dose range of 90 to 360 mg/m2. As the dose increased to 720 mg/m2, the risk increased to 22%. In irradiated patients who later received cisplatin, cumulative drug doses as low as 270 mg/m2 were associated with a high probability of substantial hearing loss, suggesting potentiation of ototoxicity when these therapies are used together. Hearing acuity was either not affected or only minimally decreased in the irradiation-only group. Younger age, prior irradiation, and the presence of a CNS tumor each contributed significantly to the severity of hearing deficits at given cisplatin dose levels. We conclude that early increases in hearing threshold at a stimulus frequency of 4,000 Hz indicate probable subsequent deficits at lower frequencies, especially in young children with CNS tumors who have received cranial irradiation. The probability charts derived from this analysis should provide a useful tool for predicting hearing loss in the speech frequencies.
Serial auditory evaluations were performed in 54 pediatric patients (5 to 18 yr) treated with cis-diamminedichloroplatinum(II) for osteosarcoma. Each course of cis-diamminedichloroplatinum(II) comprised 150 mg/m2 and was administered initially at two weekly intervals for seven courses (3 mo) and subsequently at three monthly intervals for 15 to 21 mo. Overall, 604 courses were administered, and observations were conducted from diagnosis to 6 yr. Bilateral hearing loss was detected in all patients. The loss varied from mild (20 to 40 dB) to profound (greater than 90 dB). Initial losses occurred in the higher frequencies and were also greater at these frequencies. Significant loss was first observed after 300 mg/m2 for frequencies over 4000 Hz and gradually shifted to incorporate the lower frequencies. Hearing loss was permanent.
Between January and December 1985, 17 children with advanced neuroblastoma who were greater than 1 year old (16 stage IV, one stage III) were administered cisplatin (CPDD, 200 mg/m2) and etoposide (VP-16, 500 mg/m2) as a pilot study of toxicity and response rates for the European Neuroblastoma Study Group (ENSG). The study was designed to assess toxicity of two courses of treatment, and evaluate response rates after this short therapy. The creatinine clearance declined in seven of 15 patients. No patient experienced clinically significant hearing loss, but formal audiometric assessment of nine children revealed characteristic high tone loss in seven patients. Peripheral neuropathy was not seen. Asymptomatic hypomagnesemia (less than 0.7 microEq/L) was frequent, despite routine supplementation. Asymptomatic electrolyte imbalances occurred frequently, but were generally transient. Myelosuppression was severe, but brief. Seven patients required platelet transfusions and seven were readmitted between courses due to febrile episodes while neutropenic. There were no treatment-related deaths. According to strictly defined criteria, 12 of 17 patients showed a partial response (PR), and extensive marrow evaluation showed complete clearing of disease in six of 15 patients. This high-dose regimen, if carefully supervised, is associated with acceptable toxicity, comparable to that seen when the dose of CPDD is spread over several months. The rapidity and degree of response was encouraging and merits further evaluation.
Forty-seven children or adolescents with initial stage IV (42 patients) or stage III (five) advanced neuroblastoma (12 were progressing after relapse and 35 had never reached complete remission [CR] after conventional therapy) were included in a phase II study of the combination of high-dose VP-16 (100 mg/m2/d X 5) and high-dose cisplatin (CDDP) (40 mg/m2/d X 5). Twenty patients had received prior CDDP therapy (total dose, 100 to 640 mg/m2; median, 320 mg/m2) and 38 of 47 had bone marrow involvement when included in the study. The overall response rate was 55%, with 22% CR. Duration of response was 5 to 18 months, with a median of 10 months. Eight patients are still disease free, with a median observation time of 13 months, but all had received additional therapy after two courses of this regimen. Gastrointestinal toxicity was frequent but tolerable. Myelosuppression was severe but of brief duration, ie, nadir of neutrophils was observed at day 15 with 95% of the patients recovering a normal count before day 28, and nadir of platelet count was at day 17 with only two severe and reversible episodes of bleeding. The overall incidence of sepsis was 8% (seven of 92 courses), with no death related to infection. No acute renal failure was observed after two courses, and only three of 47 children experienced a clear reduction of renal function. After two courses, only two children showed a hearing loss in the 1,000 to 2,000 Hz range, although hearing loss above the 2,000 Hz level was frequently encountered. It is concluded that high-dose VP-16 and CDDP is an effective regimen in advanced neuroblastoma with acceptable toxicity. Phase III studies are needed in previously untreated patients. J Clin Oncol 5:941-950.
The electrophysiologic and histopathologic changes in the inner ear caused by the administration of cis-diamminedichloroplatinum (CP) were studied in guinea pigs. The endocochlear dc potential (EP) gradually decreased after the intravenous injection of CP and reached approximately 0 mV on the fourth day, but the EP did not become negative. The cochlear microphonics also diminished and could not be recorded on the fourth day. The negative potential of the organ of Corti remained in the normal range during the experiment. A large negative summating potential (SP) was observed one day after injection, but the amplitude of the negative SP became small on the second day. Light microscopic examination demonstrated that the outer hair cells are destroyed in the basal turn of the cochlea and are preserved in the upper turns, while the inner hair cells are almost completely preserved in all turns. The stria vascularis was found to be slightly atrophic. Severe collapse of Reissner's membrane was observed in the basal turn.
Cis-dichlorodiammineplatinum (CDDP) and VM26, both of which have been proven efficient in treating neuroblastoma, were combined in a sequential schedule and administered to 22 children with disseminated neuroblastomas resistant to treatment with cyclophosphamide and doxorubicin (Adriamycin). During this same study, 14 children were prospectively evaluated for the effect of CDDP on magnesium metabolism and the effect of the induced hypomagnesemia on parathyroid function. Complete or partial tumor responses were achieved in six and nine cases. Respectively and were of prolonged duration (longer than six months) in eight of the 15 responding. It was also shown that CDDP-induced hypomagnesemia is the result of excessive renal loss and is severe enough to interfere with the normal parathormone response to hypocalcemia.
Pigmentation is reported to affect cisplatin-induced ototoxicity in adult humans. The hearing loss is worse in people with brown irises, than in those with blue irises. We assessed the hypothesis that cisplatintreated children with dark irises suffer more deterioration in auditory thresholds than do those with less pigmentation. For the 19 children whose data met the requirements of this observational retrospective study, we found a weak correlation (Spearman's r = 0.50; p>0.05) of high frequency hearing loss (at 4000 Hz) and pigmentation. Blue or hazel-eyed children averaged 2.9 dB worsening at 4000 Hz, in contrast to 14.2 dB worsening for brown or black-eyed children.
Pigmentation may account for some of the individual susceptibility to cisplatin ototoxicity. We suggest that iris colour be included in future reports of cisplatin-related hearing loss
Adjuvant chemotherapy has improved the outcome of childhood malignant brain tumors in large randomized trials. With increasing survival rates, treatment toxicity has become a matter of concern. Radiation therapy and cisplatinum are known to be ototoxic.
We evaluated the incidence and factors predisposing to ototoxicity in children treated with the "8 in 1" chemotherapy protocol in Finland during 1986--1993. Thirty-five of the 82 children survived for at least 1 year after diagnosis. Thirty of these children were old enough to have an audiogram.
Seventeen of the 30 children had normal hearing, seven had hearing loss at high frequencies, and six (20%) had severe hearing loss in the speech range. The risk factors for severe hearing loss were young age, a high cumulative dose of cisplatinum, and deteriorating renal function. In the presence of these factors, the risk of severe hearing loss was over 50%. Hearing loss at high frequencies could occur after low cumulative doses of cisplatinum, but severe hearing loss correlated with high cumulative doses.
Cisplatinum-induced hearing loss at high frequencies is common, but hearing loss in the speech range also occurs, particularly in children with predisposing factors, and may progress insidiously and rapidly. Therefore a hearing test before each "8 in 1" course is important.
We reviewed and re-examined 31 children (6 months-14 years at the time of diagnosis), who had been treated for a neoplasm in Turku University Central Hospital between 1989 and 1994. The children were divided into 3 groups according to the site of the neoplasm and the type of therapy. Group I included 13 children, operated on for an intracranial tumor and received postoperative radio- and cisplatin-based chemotherapy. Group II included 14 children operated on for intracranial tumors and treated with radiotherapy, but not given chemotherapy. Group III included 4 children suffering from extracranial malignancies and they had received chemotherapy including cisplatin. The children in Group I had significantly worse hearing thresholds in the middle- and high-frequency range than children in Groups II and III. In a precise analysis of the different factors, no single dose of cisplatin, inner ear irradiation dose or totally to the central nervous system (CNS) received irradiation dose correlated to the detected hearing loss. However, multiple linear correlation analyses suggest a combined effect of radiotherapy plus cisplatin resulting in a high frequency hearing loss. This is in accordance with earlier random case reports, and supports the idea that radiotherapy should be considered cautiously in children treated with cisplatin for intracranial malignancies.
Advances in chemotherapy and supportive care have slowly improved survival rates for patients with high-risk neuroblastoma. The focus of many of these chemotherapeutic advances has been dose intensification. In this phase II trial involving children with advanced neuroblastoma, we used a program of induction chemotherapy followed by tandem high-dose, myeloablative treatments (high-dose therapy) with stem-cell rescue (HDT/SCR) in rapid sequence.
Patients underwent induction chemotherapy during which peripheral-blood stem and progenitor cells were collected and local control measures undertaken. Patients then received tandem courses of HDT/SCR, 4 to 6 weeks apart. Thirty-nine patients (age 1 to 12 years) were assessable, and 70 cycles of HDT/SCR were completed.
Pheresis was possible in the case of all patients, despite their young ages, with an average of 7.2 x 10(6) CD34(+) cells/kg available to support each cycle. Engraftment was rapid; median time to neutrophil engraftment was 11 days. Four patients who completed the first HDT course did not complete the second, and there were three deaths due to toxicity. With a median follow-up of 22 months (from diagnosis), 26 of 39 patients remained event-free. The 3-year event-free survival rate for these patients was 58%.
A tandem HDT/SCR regimen for high-risk neuroblastoma is a feasible treatment strategy for children and may improve disease-free survival.
Hepatoblastoma (HB) is a rare malignant liver tumor which occurs almost exclusively in childhood. In the 1970s, survival was approximately 20% to 30%. Since the introduction of cisplatin (PLA) and doxorubicin (DO) into the chemotherapy regimens used to treat these patients, the survival rate has improved dramatically. In most recent studies, primary surgery preceded chemotherapy. In this study by the liver group of the International Society of Pediatric Oncology the aim was to improve survival and reduce operative morbidity and mortality by using preoperative chemotherapy.
After biopsy and assessment of pretreatment extent of disease all patients were treated with continuous 24-hour intravenous infusion of PLA 80 mg/m(2) followed by DO 60 mg/m(2) over 48 hours (PLADO). After four courses of this chemotherapy, patients were reassessed. Where possible, the primary tumor was resected and treatment completed with two more courses of chemotherapy.
One hundred fifty-four patients were registered in the study, and 138 received preoperative chemotherapy. One hundred thirteen (82%) showed a partial response with tumor shrinkage and serial decrease of serum alpha-fetoprotein levels. One hundred fifteen patients had delayed surgery, and 106 (including six with liver transplants) had complete resection of primary tumor. Five-year event-free survival was 66%, and overall survival was 75%.
This study demonstrates that international collaboration on a large scale is feasible. The toxicity of chemotherapy and morbidity of surgery were acceptable and the overall survival gratifyingly high. We now regard PLADO chemotherapy and delayed surgery to be the best available treatment for children with HB. Other treatment programs should be measured against this standard.
To investigate whether intensive induction therapy followed by triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue and local irradiation will improve event-free survival for patients with high-risk neuroblastoma.
From August 1995 to January 2000, 25 consecutive newly diagnosed high-risk neuroblastoma patients and one child with recurrent MYCN-amplified disease were enrolled onto the Chicago Pilot II Protocol. After induction therapy and surgery, peripheral-blood stem cells were mobilized with three cycles of high-dose cyclophosphamide and granulocyte colony-stimulating factor. Patients then underwent triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue followed by radiation to the primary site.
Twenty-two of the 26 patients successfully completed induction therapy and were eligible for the triple-tandem consolidation high-dose therapy. Sufficient numbers of peripheral-blood stem cells were collected in all but one patient. Seventeen patients were able to complete all three cycles of high-dose therapy and peripheral-blood stem-cell rescue, two patients completed two cycles, and three patients completed one cycle. There was one toxic death, and one patient died from complications of treatment for graft failure. With a median follow-up of 38 months, the 3-year event-free survival and survival rates are 57% +/- 11% and 79% +/- 10%, respectively.
The results of this pilot study demonstrate that it is feasible to intensify consolidation with triple-tandem high-dose chemotherapy and peripheral-blood stem-cell rescue and local irradiation, and suggest that this treatment strategy may lead to improved survival for patients with high-risk neuroblastoma.
Platinum compound based chemotherapy has contributed to improved survival rates in neuroblastoma patients. We studied the association of hearing loss with the use of platinum based drugs.
Data of children from the two German neuroblastoma study cohorts, NB90 and NB97, were analyzed for the incidence of hearing impairments greater than WHO grade 2. Data from patients surviving more than 1 year after diagnosis without progression or recurrence were used.
Of these 1,170 patients, 146 (12.5 %) had persisting hearing impairments. The incidence was low after localized neuroblastoma INSS stage 1 - 3 with 35/650 (5 %) and stage 4S with 2/113 (2 %), but high in stage 4 disease with 109/405 (27 %). Ototoxicity depended on the cumulative cisplatin dose. For doses of 1 - 200 mg/m (2), 201 - 400 mg/m (2), 401 - 600 mg/m (2) and 601 - 800 mg/m (2) we found hearing impairments in 5/39 (12 %), 28/221 (13 %), 61/230 (26 %) and 50/225 (22 %) patients, respectively. The incidence of hearing impairment was not age dependent. In stage 4 patients, there was an additional effect of high dosed carboplatin. 65/188 (40 %) patients developed hearing impairments after carboplatin containing (1,500 mg/m (2)) high dose chemotherapy with autologous stem cell reinfusion compared to only 33/217 (15 %) in patients receiving platinum free maintenance chemotherapy. Substitution of cisplatin (40 mg/m (2) x d, d 1 - 4, 96 h infusion) with carboplatin (100 mg/m (2) x d, d 1 - 4, 1 - 2 h infusion) due to otoxicity during induction chemotherapy did not reduce event free survival.
One fourth of high risk neuroblastoma survivors suffer from treatment induced hearing impairments. The substitution of cisplatin with carboplatin was not associated with an increased rate of tumor recurrences.
The aim of this study was to determine the risk factors for high-frequency hearing loss in children treated with cisplatin. We scored off-treatment pure-tone audiograms from 153 children (age 6 months to 18 years) who had completed cisplatin therapy (40-200 mg/m(2)/cycle) for germ cell tumours, hepatoblastoma, neuroblastoma or osteosarcoma. The risk of developing bilateral moderate to severe high-frequency hearing loss was significantly related to the age at treatment (P<0.001), and individual and cumulative cisplatin dosages (both P<0.005). Logistic regression showed that children younger than 5 years were at a greater risk of sustaining cisplatin ototoxicity than children older than 15 years, controlling for individual and cumulative doses of cisplatin (Odds Ratio (OR)=21.17, 95% Confidence Interval (CI): 2.48-180.94). Age at treatment and the cumulative dose of cisplatin were the two most important risk factors in predicting moderate to severe high-frequency hearing loss in children treated with cisplatin.
We previously reported a high response rate with a dose-intensive chemotherapy regimen in 24 children with high-risk neuroblastoma (NB). We now describe similar results with changes that reduce toxicity (fewer cycles, less vincristine, use of granulocyte colony-stimulating factor).
Eighty-seven consecutive newly diagnosed children with high-risk NB underwent induction that initially had seven cycles (57 patients) but was later limited to five (30 patients). Cycles 1, 2, 4, and 6 used cyclophosphamide (140 mg/kg)/doxorubicin (75 mg/m(2))/vincristine (0.15 mg/kg in the first 27 patients, 0.067 mg/kg subsequently). Cycles 3, 5, and 7 used cisplatin (200 mg/m(2))/etoposide (600 mg/m(2)). Tumor resection followed a minimum of three cycles. The induction was eventually modified to include anti-G(D2) immunotherapy after each of the last three cycles (38 patients).
Bone marrow disease resolved in 70 (91%) of 77 patients and was not detected pre- and postinduction in 10 patients. After cycle 3 or 4, 86% of primary tumors were more than 50% smaller. Postinduction metaiodobenzylguanidine scans showed normal radiotracer distribution in metastatic sites in 74 (87%) of 85 patients. Overall results were: 68 (79%) complete/very good partial responses (CR/VGPR); 14 (16%) partial responses (PR); three (3%) less than PR; one (1%) death from infection; and one patient not assessable for response. Five cycles yielded a CR/VGPR rate of 83%, compared with a 77% rate from seven cycles. Side effects were myelosuppression, mucositis, and hearing deficits; neurotoxicity was insignificant with the lower vincristine dosage. Four patients (each received seven cycles) developed myelodysplasia/leukemia.
Five cycles of this induction regimen, plus surgery, suffice to achieve CR/VGPR in approximately 80% of children with high-risk NB.
The aim of this study was to analyze cisplatin-induced ototoxicity in a recent study trial. Seventy-four patients who had received cisplatin for the treatment of osteosarcoma (median cumulative dose: 360 mg/m2) were investigated prospectively for ototoxicity in a multicenter trial. Hearing function was tested by audiometry. We evaluated the incidence and dependencies of hearing loss. After cessation of therapy, 51% of the patients showed a hearing loss of >20 dB in the frequency range of 4-8 kHz. Only in one patient a hearing loss was found at 2 kHz, and in none at 1 kHz. At a cumulative cisplatin dose of < or = 240 mg/m2, almost no ototoxicity was found. Incidence and magnitude of hearing loss increased significantly with a higher cumulative dose. Furthermore, hearing thresholds were significantly poorer in children <12 years. A further follow-up investigation showed only a marginal change in hearing function. We conclude that ototoxicity is moderate in our group of patients and probably irreversible.
To describe the frequency and severity of ototoxicity in a series of pediatric patients treated with platinum-based chemotherapy.
Serial audiologic evaluations were conducted for 67 patients aged 8 months to 23 years who received platinum-based chemotherapy. Audiologic data was analyzed to determine time to hearing-loss using American Speech-Language-Hearing Association (ASHA) criteria, and the effects of treatment and patient characteristics on the incidence and severity of ototoxicity.
Bilateral decreases in hearing were seen in 61% of patients (median time to hearing loss, 135 days). Children treated for medulloblastoma, osteosarcoma, and neuroblastoma had greater incidence and severity of hearing loss. Agreement between the usually reported National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and ASHA criteria was inadequate.
Traditional reporting of toxicity data (CTCAE) has under-reported ototoxicity and minimized the significance of hearing loss in children. As pediatric patients experience improved survival, the effects and implications of high-frequency hearing loss with regard to academic achievement and speech and language development are important considerations, especially in patients younger than 5 years.
Phase I trial ofcarboplatin, etoposide, melphalan and local irradiation (CEM‐LI) with purged autologous bone marrow transplantation for children with high‐risk neuroblastoma
- Villablanca JG
Villablanca JG, Matthay KK, Swift PS, et al. Phase I trial
of carboplatin, etoposide, melphalan and local irradiation
(CEM-LI) with purged autologous bone marrow transplantation for children with high-risk neuroblastoma. Med
Pediatr Oncol. 1999;33:170. Abstract.
Auditory function in pediatric osteosarcoma patients treated with multiple doses of cis-diamminedichloroplatinum (II) Cisplatin-induced ototoxicity in osteosarcoma patients: A report from the late effects surveillance system
- L Ruiz
- J Golden
- N Jaffe
- R Robertson
- Wang
- W Stöhr
- T Langer
- Kremers
Ruiz L, Golden J, Jaffe N, Robertson R, Wang YM. Auditory function in pediatric osteosarcoma patients treated with multiple doses of cis-diamminedichloroplatinum (II). Cancer Res. 1989;49:742–744. 14. Stöhr W, Langer T, Kremers A. Cisplatin-induced ototoxicity in osteosarcoma patients: A report from the late effects surveillance system. Cancer Invest. 2005;23:201–207.